Pharmaceutical compositions

ABSTRACT

Provided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/820,499, filed onJun. 19, 2007, which claims priority to U.S. 60/814,949, filed on Jun.19, 2006.

FIELD OF THE INVENTION

This invention pertains to a sequestering subunit comprising anantagonist and a blocking agent, and related compositions and methods ofuse, such as in the prevention of abuse of a therapeutic agent.

BACKGROUND OF THE INVENTION

Opioids, also called opioid agonists, are a class of drugs that exhibitopium-like or morphine-like properties. The opioids are employedprimarily as moderate to strong analgesics, but have many otherpharmacological effects as well, including drowsiness, respiratorydepression, changes in mood, and mental clouding without a resultingloss of consciousness. Because of these other pharmacological effects,opioids have become the subject of dependence and abuse. Therefore, amajor concern associated with the use of opioids is the diversion ofthese drugs from the illicit user, e.g., an addict.

Physical dependence may develop upon repeated administrations orextended use of opioids. Physical dependence is gradually manifestedafter stopping opioid use or is precipitously manifested (e.g., within afew minutes) after administration of a narcotic antagonist (referred to“precipitated withdrawal”). Depending upon the drug upon whichdependence has been established and the duration of use and dose,symptoms of withdrawal vary in number and kind, duration and severity.The most common symptoms of the withdrawal syndrome include anorexia,weight loss, pupillary dilation, chills alternating with excessivesweating, abdominal cramps, nausea, vomiting, muscle spasms,hyperirritability, lacrimation, rinorrhea, goose flesh and increasedheart rate. Natural abstinence syndromes typically begin to occur 24-48hours after the last dose, reach maximum intensity about the third dayand may not begin to decrease until the third week. Precipitatedabstinence syndromes produced by administration of an opioid antagonistvary in intensity and duration with the dose and the specificantagonist, but generally vary from a few minutes to several hours inlength.

Psychological dependence or addiction to opioids is characterized bydrug-seeking behavior directed toward achieving euphoria and escapefrom, e.g., psychosocioeconomic pressures. An addict will continue toadminister opioids for non-medicinal purposes and in the face ofself-harm.

Although opioids, such as morphine, hydromorphone, hydrocodone andoxycodone, are effective in the management of pain, there has been anincrease in their abuse by individuals who are psychologically dependenton opioids or who misuse opioids for non-therapeutic reasons. Previousexperience with other opioids has demonstrated a decreased abusepotential when opioids are administered in combination with a narcoticantagonist, especially in patients who are ex-addicts (Weinhold et al.,Drug and Alcohol Dependence 30:263-274 (1992); and Mendelson et al.,Clin. Pharm. Ther. 60:105-114 (1996)). These combinations, however, donot contain the opioid antagonist that is in a sequestered form. Rather,the opioid antagonist is released in the gastrointestinal system whenorally administered and is made available for absorption, relying on thephysiology of the host to metabolize differentially the agonist andantagonist and negate the agonist effects.

Previous attempts to control the abuse potential associated with opioidanalgesics include, for example, the combination of pentazocine andnaloxone in tablets, commercially available in the United States asTalwin®Nx from Sanofi-Winthrop, Canterbury, Australia. Talwin®Nxcontains pentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. Talwin®Nx is indicated for therelief of moderate to severe pain. The amount of naloxone present inthis combination has low activity when taken orally, and minimallyinterferes with the pharmacologic action of pentazocine. However, thisamount of naloxone given parenterally has profound antagonistic actionto narcotic analgesics. Thus, the inclusion of naloxone is intended tocurb a form of misuse of oral pentazocine, which occurs when the dosageform is solubilized and injected. Therefore, this dosage has lowerpotential for parenteral misuse than previous oral pentazocineformulations. However, it is still subject to patient misuse and abuseby the oral route, for example, by the patient taking multiple doses atonce. A fixed combination therapy comprising tilidine (50 mg) andnaloxone (4 mg) has been available in Germany for the management ofsevere pain since 1978 (Valoron®N, Goedecke). The rationale for thecombination of these drugs is effective pain relief and the preventionof tilidine addiction through naloxone-induced antagonisms at thetilidine receptors. A fixed combination of buprenorphine and naloxonewas introduced in 1991 in New Zealand (Terngesic®Nx, Reckitt & Colman)for the treatment of pain.

International Patent Application No. PCT/US01/04346 (WO 01/58451) toEuroceltique, S.A., describes the use of a pharmaceutical compositionthat contains a substantially non-releasing opioid antagonist and areleasing opioid agonist as separate subunits that are combined into apharmaceutical dosage form, e.g., tablet or capsule. However, becausethe agonist and antagonist are in separate subunits, they can be readilyseparated. Further, providing the agonist and antagonist as separatesubunits, tablets are more difficult to form due to the mechanicalsensitivity of some subunits comprising a sequestering agent.

The benefits of the abuse-resistant dosage form are especially great inconnection with oral dosage forms of strong opioid agonists (e.g.,morphine, hydromorphone, oxycodone or hydrocodone), which providevaluable analgesics but are prone to being abused. This is particularlytrue for sustained-release opioid agonist products, which have a largedose of a desirable opioid agonist intended to be released over a periodof time in each dosage unit. Drug abusers take such sustained releaseproduct and crush, grind, extract or otherwise damage the product sothat the full contents of the dosage form become available for immediateabsorption.

Such abuse-resistant, sustained-release dosage forms have been describedin the art (see, for example, U.S. Application Nos. 2003/0124185 and2003/0044458). However, it is believed that substantial amounts of theopioid antagonist or other antagonist found in these sequestered formsare released over time (usually less than 24 hours) due to the osmoticpressure that builds up in the core of the sequestered form, as waterpermeates through the sequestered form into the core. The high osmoticpressure inside the core of the sequestered form causes the opioidantagonist or antagonist to be pushed out of the sequestered form,thereby causing the opioid antagonist or antagonist to be released fromthe sequestered form.

In view of the foregoing drawbacks of the sequestered forms of the priorart, there exists a need in the art for a sequestered form of an opioidantagonist or other antagonist that is not substantially released fromthe sequestered form due to osmotic pressure. The invention providessuch a sequestering form of an opioid antagonist or antagonist. This andother objects and advantages of the invention, as well as additionalinventive features, will be apparent from the description of theinvention provided herein.

BRIEF SUMMARY OF THE INVENTION

Provided herein is a pharmaceutical composition comprising anantagonist, an agonist, a seal coat, and a sequestering polymer, whereinthe antagonist, agonist, seal coat and at least one sequestering polymerare all components of a single unit, and wherein the seal coat forms alayer physically separating the antagonist from the agonist from oneanother. In one embodiment, a multi-layer pharmaceutical compositioncomprising an agonist and an antagonist thereof, wherein the agonist andantagonist are not in contact with one another in the intact form of thecomposition, wherein the agonist is substantially released and theantagonist is substantially sequestered upon administration to a humanbeing is provided. Methods for manufacturing such a pharmaceuticalcomposition are also provided. In another embodiment, a method formeasuring the amount of antagonist or derivative thereof in a biologicalsample, the antagonist or derivative having been released from apharmaceutical composition in vivo, the method comprising the USP paddlemethod at 37° C., 100 rpm, but further comprising incubation in a buffercontaining a surfactant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Naltrexone (NT) release from Eudragit® RS-coated pellets withoutSLS.

FIG. 2. Effect of SLS levels in Eudragit® RS coat on naltrexone (NT)release.

FIG. 3. Effect of SLS levels in Eudragit® RS coat on naltrexone (NT)release.

FIG. 4. Effect of talc levels in Eudragit® RS coat on naltrexone (NT)release.

FIG. 5. Naltrexone dissolution profile vs. Eudragit® RS neutralizationat 26% (v/v) talc.

FIG. 6. Naltrexone dissolution profile vs. talc level at 41% Eudragit®RS neutralization.

FIG. 7. Plasma naltrexone levels for naltrexone (NTX) solution.

FIG. 8. Plasma 6-beta-naltrexol levels for naltrexone (NTX) solution.

FIG. 9. Plasma naltrexone levels for PI-1460 and PI-1461.

FIG. 10. Plasma 6-beta naltrexol levels for PI-1460 and PI-1461.

FIG. 11. Plasma naltrexone levels for PI-1462 and PI-1463.

FIG. 12. Plasma 6-beta-naltrexol levels for PI-1462 and PI-1463.

FIG. 13. Percent naltrexone (NT) release for PI-1465 and PI-1466.

FIG. 14. Plasma naltrexone levels for PI-1465 and PI-1466.

FIG. 15. Plasma 6-beta-naltrexol levels for PI-1465 and PI-1466.

FIG. 16. Plasma naltrexone levels for PI-1465 and PI-1466 (fast andfed).

FIG. 17. Plasma 6-beta-naltrexol levels for PI-1465 and PI-1466 (fastand fed).

FIG. 18. Plasma naltrexone levels for PI-1495 and PI-1496 (fast andfed).

FIG. 19. Plasma 6-beta-naltrexol levels for PI-1495 and PI-1496 (fastand fed).

FIG. 20. Plasma naltrexone levels for PI-1510 (fast and fed).

FIG. 21. Plasma 6-beta-naltrexol levels for PI-1510 (fast and fed).

FIGS. 22 A and B. Exemplary manufacturing process for multi-layernaltrexone-morphine pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compositions and methods for administering amultiple active agents to a mammal in a form and manner that minimizesthe effects of either active agent upon the other in vivo. In certainembodiments, at least two active agents are formulated as part of apharmaceutical composition. A first active agent may provide atherapeutic effect in vivo. The second active agent may be an antagonistof the first active agent, and may be useful in preventing misuse of thecomposition. For instance, where the first active agent is a narcotic,the second active agent may be an antagonist of the narcotic. Thecomposition remains intact during normal usage by patients and theantagonist is not released. However, upon tampering with thecomposition, the antagonist may be released thereby preventing thenarcotic from having its intended effect. In certain embodiments, theactive agents are both contained within a single unit, such as a bead,in the form of layers. The active agents may be formulated with asubstantially impermeable barrier as, for example, a controlled-releasecomposition, such that release of the antagonist from the composition isminimized. In certain embodiments, the antagonist is released in invitro assays but is substantially not released in vivo. In vitro and invivo release of the active agent from the composition may be measured byany of several well-known techniques. For instance, in vivo release maybe determined by measuring the plasma levels of the active agent ormetabolites thereof (i.e., AUC, Cmax).

In one embodiment, the invention provides a sequestering subunitcomprising an opioid antagonist and a blocking agent, wherein theblocking agent substantially prevents release of the opioid antagonistfrom the sequestering subunit in the gastrointestinal tract for a timeperiod that is greater than 24 hours. This sequestering subunit isincorporated into a single pharmaceutical unit that also includes anopioid agonist. The pharmaceutical unit thus includes a core portion towhich the opioid antagonist is applied. A seal coat is then optionallyapplied upon the antagonist. Upon the seal coat is then applied acomposition comprising the pharmaceutically active agent. An additionallayer containing the same or a different blocking agent may then beapplied such that the opioid agonist is released in the digestive tractover time (i.e., controlled release). Thus, the opioid antagonist andthe opioid agonist are both contained within a single pharmaceuticalunit, which is typically in the form of a bead.

The term “sequestering subunit” as used herein refers to any means forcontaining an antagonist and preventing or substantially preventing therelease thereof in the gastrointestinal tract when intact, i.e., whennot tampered with. The term “blocking agent” as used herein refers tothe means by which the sequestering subunit is able to preventsubstantially the antagonist from being released. The blocking agent maybe a sequestering polymer, for instance, as described in greater detailbelow.

The terms “substantially prevents,” “prevents,” or any words stemmingtherefrom, as used herein, means that the antagonist is substantiallynot released from the sequestering subunit in the gastrointestinaltract. By “substantially not released” is meant that the antagonist maybe released in a small amount, but the amount released does not affector does not significantly affect the analgesic efficacy when the dosageform is orally administered to a host, e.g., a mammal (e.g., a human),as intended. The terms “substantially prevents,” “prevents,” or anywords stemming therefrom, as used herein, does not necessarily imply acomplete or 100% prevention. Rather, there are varying degrees ofprevention of which one of ordinary skill in the art recognizes ashaving a potential benefit. In this regard, the blocking agentsubstantially prevents or prevents the release of the antagonist to theextent that at least about 80% of the antagonist is prevented from beingreleased from the sequestering subunit in the gastrointestinal tract fora time period that is greater than 24 hours. Preferably, the blockingagent prevents release of at least about 90% of the antagonist from thesequestering subunit in the gastrointestinal tract for a time periodthat is greater than 24 hours. More preferably, the blocking agentprevents release of at least about 95% of the antagonist from thesequestering subunit. Most preferably, the blocking agent preventsrelease of at least about 99% of the antagonist from the sequesteringsubunit in the gastrointestinal tract for a time period that is greaterthan 24 hours.

For purposes of this invention, the amount of the antagonist releasedafter oral administration can be measured in-vitro by dissolutiontesting as described in the United States Pharmacopeia (USP26) inchapter <711> Dissolution. For example, using 900 mL of 0.1 N HCl,Apparatus 2 (Paddle), 75 rpm, at 37° C. to measure release at varioustimes from the dosage unit. Other methods of measuring the release of anantagonist from a sequestering subunit over a given period of time areknown in the art (see, e.g., USP26).

Without being bound to any particular theory, it is believed that thesequestering subunit of the invention overcomes the limitations of thesequestered forms of an antagonist known in the art in that thesequestering subunit of the invention reduces osmotically-driven releaseof the antagonist from the sequestering subunit. Furthermore, it isbelieved that the present inventive sequestering subunit reduces therelease of the antagonist for a longer period of time (e.g., greaterthan 24 hours) in comparison to the sequestered forms of antagonistsknown in the art. The fact that the sequestered subunit of the inventionprovides a longer prevention of release of the antagonist isparticularly relevant, since precipitated withdrawal could occur afterthe time for which the therapeutic agent is released and acts. It iswell known that the gastrointestinal tract transit time for individualsvaries greatly within the population. Hence, the residue of the dosageform may be retained in the tract for longer than 24 hours, and in somecases for longer than 48 hours. It is further well known that opioidanalgesics cause decreased bowel motility, further prolonginggastrointestinal tract transit time. Currently, sustained-release formshaving an effect over a 24 hour time period have been approved by theFood and Drug Administration. In this regard, the present inventivesequestering subunit provides prevention of release of the antagonistfor a time period that is greater than 24 hours when the sequesteringsubunit has not been tampered.

The sequestering subunit of the invention is designed to preventsubstantially the release of the antagonist when intact. By “intact” ismeant that a dosage form has not undergone tampering. The term“tampering” is meant to include any manipulation by mechanical, thermaland/or chemical means, which changes the physical properties of thedosage form. The tampering can be, for example, crushing, shearing,grinding, chewing, dissolution in a solvent, heating (for example,greater than about 45° C.), or any combination thereof. When thesequestering subunit of the invention has been tampered with, theantagonist is immediately released from the sequestering subunit.

By “subunit” is meant to include a composition, mixture, particle; etc.,that can provide a dosage form (e.g., an oral dosage form) when combinedwith another subunit. The subunit can be in the form of a bead, pellet,granule, spheroid, or the like, and can be combined with additional sameor different subunits, in the form of a capsule, tablet or the like, toprovide a dosage form, e.g., an oral dosage form. The subunit may alsobe part of a larger, single unit, forming part of that unit, such as alayer. For instance, the subunit may be a core coated with an antagonistand a seal coat; this subunit may then be coated with additionalcompositions including a pharmaceutically active agent such as an opioidagonist.

By “antagonist of a therapeutic agent” is meant any drug or molecule,naturally-occurring or synthetic that binds to the same target molecule(e.g., a receptor) of the therapeutic agent, yet does not produce atherapeutic, intracellular, or in vivo response. In this regard, theantagonist of a therapeutic agent binds to the receptor of thetherapeutic agent, thereby preventing the therapeutic agent from actingon the receptor. In the case of opioids, an antagonist may prevent theachievement of a “high” in the host.

The antagonist can be any agent that negates the effect of thetherapeutic agent or produces an unpleasant or punishing stimulus oreffect, which will deter or cause avoidance of tampering with thesequestering subunit or compositions comprising the same. Desirably, theantagonist does not harm a host by its administration or consumption buthas properties that deter its administration or consumption, e.g., bychewing and swallowing or by crushing and snorting, for example. Theantagonist can have a strong or foul taste or smell, provide a burningor tingling sensation, cause a lachrymation response, nausea, vomiting,or any other unpleasant or repugnant sensation, or color tissue, forexample. Preferably, the antagonist is selected from the groupconsisting of an antagonist of a therapeutic agent, a bittering agent, adye, a gelling agent, and an irritant. Exemplary antagonists includecapsaicin, dye, bittering agents and emetics. The antagonist cancomprise a single type of antagonist (e.g., a capsaicin), multiple formsof a single type of antagonist (e.g., a capasin and an analoguethereof), or a combination of different types of antagonists (e.g., oneor more bittering agents and one or more gelling agents). Desirably, theamount of antagonist in the sequestering subunit of the invention is nottoxic to the host.

In the instance when the therapeutic agent is an opioid agonist, theantagonist preferably is an opioid antagonist, such as naltrexone,naloxone, nalmefene, cyclazacine, levallorphan, derivatives or complexesthereof, pharmaceutically acceptable salts thereof, and combinationsthereof. More preferably, the opioid antagonist is naloxone ornaltrexone. By “opioid antagonist” is meant to include one or moreopioid antagonists, either alone or in combination, and is further meantto include partial antagonists, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers thereof, esters thereof, andcombinations thereof. The pharmaceutically acceptable salts includemetal salts, such as sodium salt, potassium salt, cesium salt, and thelike; alkaline earth metals, such as calcium salt, magnesium salt, andthe like; organic amine salts, such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, and the like;inorganic acid salts, such as hydrochloride, hydrobromide, sulfate,phosphate, and the like; organic acid salts, such as formate, acetate,trifluoroacetate, maleate, tartrate, and the like; sulfonates, such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts, such as arginate, asparginate, glutamate, and thelike. In certain embodiments, the amount of the opioid antagonist can beabout 10 ng to about 275 mg. In a preferred embodiment, when theantagonist is naltrexone, it is preferable that the intact dosage formreleases less than 0.125 mg or less within 24 hours, with 0.25 mg orgreater of naltrexone released after 1 hour when the dosage form iscrushed or chewed.

In a preferred embodiment, the opioid antagonist comprises naloxone.Naloxone is an opioid antagonist, which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to block completely the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver, such that it has been reported to havesignificantly lower potency than when parenterally administered. Oraldosages of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed (Weinberg et al., Clin.Pharmacol. Ther. 44:335-340 (1988)).

In another preferred embodiment, the opioid antagonist comprisesnaltrexone. In the treatment of patients previously addicted to opioids,naltrexone has been used in large oral doses (over 100 mg) to preventeuphorigenic effects of opioid agonists. Naltrexone has been reported toexert strong preferential blocking action against mu over delta sites.Naltrexone is known as a synthetic congener of oxymorphone with noopioid agonist properties, and differs in structure from oxymorphone bythe replacement of the methyl group located on the nitrogen atom ofoxymorphone with a cyclopropylmethyl group. The hydrochloride salt ofnaltrexone is soluble in water up to about 100 mg/cc. Thepharmacological and pharmacokinetic properties of naltrexone have beenevaluated in multiple animal and clinical studies. See, e.g., Gonzalezet al. Drugs 35:192-213 (1988). Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont(Wilmington, Del.)) for the treatment of alcohol dependence and for theblockade of exogenously administered opioids. See, e.g., Revia(naltrexone hydrochloride tablets), Physician's Desk Reference, 51^(st)ed., Montvale, N.J.; and Medical Economics 51:957-959 (1997). A dosageof 50 mg Revia® blocks the pharmacological effects of 25 mg IVadministered heroin for up to 24 hours. It is known that, whencoadministered with morphine, heroin or other opioids on a chronicbasis, naltrexone blocks the development of physical dependence toopioids. It is believed that the method by which naltrexone blocks theeffects of heroin is by competitively binding at the opioid receptors.Naltrexone has been used to treat narcotic addiction by completeblockade of the effects of opioids. It has been found that the mostsuccessful use of naltrexone for a narcotic addiction is with narcoticaddicts having good prognosis, as part of a comprehensive occupationalor rehabilitative program involving behavioral control or othercompliance-enhancing methods. For treatment of narcotic dependence withnaltrexone, it is desirable that the patient be opioid-free for at least7-10 days. The initial dosage of naltrexone for such purposes hastypically been about 25 mg, and if no withdrawal signs occur, the dosagemay be increased to 50 mg per day. A daily dosage of 50 mg is consideredto produce adequate clinical blockade of the actions of parenterallyadministered opioids. Naltrexone also has been used for the treatment ofalcoholism as an adjunct with social and psychotherapeutic methods.Other preferred opioid antagonists include, for example, cyclazocine andnaltrexone, both of which have cyclopropylmethyl substitutions on thenitrogen, retain much of their efficacy by the oral route, and lastlonger, with durations approaching 24 hours after oral administration.

The antagonist may also be a bittering agent. The term “bittering agent”as used herein' refers to any agent that provides an unpleasant taste tothe host upon inhalation and/or swallowing of a tampered dosage formcomprising the sequestering subunit. With the inclusion of a bitteringagent, the intake of the tampered dosage form produces a bitter tasteupon inhalation or oral administration, which, in certain embodiments,spoils or hinders the pleasure of obtaining a high from the tampereddosage form, and preferably prevents the abuse of the dosage form.

Various bittering agents can be employed including, for example, andwithout limitation, natural, artificial and synthetic flavor oils andflavoring aromatics and/or oils, oleoresins and extracts derived fromplants, leaves, flowers, fruits, and so forth, and combinations thereof.Non-limiting representative flavor oils include spearmint oil,peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil ofbitter almonds, menthol and the like. Also useful bittering agents areartificial, natural and synthetic fruit flavors such as citrus oils,including lemon, orange lime, and grapefruit, fruit essences, and soforth. Additional bittering agents include sucrose derivatives (e.g.,sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, andthe like. A preferred bittering agent for use in the invention isDenatonium Benzoate NF-Anhydrous, sold under the name Bitrex™ (MacfarlanSmith Limited, Edinburgh, UK). A bittering agent can be added to theformulation in an amount of less than about 50% by weight, preferablyless than about 10% by weight, more preferably less than about 5% byweight of the dosage form, and most preferably in an amount ranging fromabout 0.1 to 1.0 percent by weight of the dosage form, depending on theparticular bittering agent(s) used.

Alternatively, the antagonist may be a dye. The term “dye” as usedherein refers to any agent that causes discoloration of the tissue incontact. In this regard, if the sequestering subunit is tampered withand the contents are snorted, the dye will discolor the nasal tissuesand surrounding tissues thereof. Preferred dyes are those that can bindstrongly with subcutaneous tissue proteins and are well-known in theart. Dyes useful in applications ranging from, for example, foodcoloring to tattooing, are exemplary dyes suitable for the invention.Food coloring dyes include, but are not limited to FD&C Green #3 andFD&C Blue #1, as well as any other FD&C or D&C color. Such food dyes arecommercially available through companies, such as Voigt GlobalDistribution (Kansas City, Mo.).

The antagonist may alternatively be an irritant. The term “irritant” asused herein includes a compound used to impart an irritating, e.g.,burning or uncomfortable, sensation to an abuser administering atampered dosage form of the invention. Use of an irritant willdiscourage an abuser from tampering with the dosage form and thereafterinhaling, injecting, or swallowing the tampered dosage form. Preferably,the irritant is released when the dosage form is tampered with andprovides a burning or irritating effect to the abuser upon inhalation,injection, and/or swallowing the tampered dosage form. Various irritantscan be employed including, for example, and without limitation,capsaicin, a capsaicin analog with similar type properties as capsaicin,and the like. Some capsaicin analogues or derivatives include, forexample, and without limitation, resiniferatoxin, tinyatoxin,heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides orguaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoylvanillylamide, or other compounds of the class known as vanilloids.Resiniferatoxin is described, for example, in U.S. Pat. No. 5,290,816.U.S. Pat. No. 4,812,446 describes capsaicin analogs and methods fortheir preparation. Furthermore, U.S. Pat. No. 4,424,205 cites Newman,“Natural and Synthetic Pepper-Flavored Substances,” published in 1954 aslisting pungency of capsaicin-like analogs. Ton et al., British Journalof Pharmacology 10:175-182 (1955), discusses pharmacological actions ofcapsaicin and its analogs. With the inclusion of an irritant (e.g.,capsaicin) in the dosage form, the irritant imparts a burning ordiscomforting quality to the abuser to discourage the inhalation,injection, or oral administration of the tampered dosage form, andpreferably to prevent the abuse of the dosage form. Suitable capsaicincompositions include capsaicin (trans 8-methyl-N-vanillyl-6-noneamide)or analogues thereof in a concentration between about 0.00125% and 50%by weight, preferably between about 1% and about 7.5% by weight, andmost preferably, between about 1% and about 5% by weight.

The antagonist may also be a gelling agent. The term “gelling agent” asused herein refers to any agent that provides a gel-like quality to thetampered dosage form, which slows the absorption of the therapeuticagent, which is formulated with the sequestering subunit, such that ahost is less likely to obtain a rapid “high.” In certain preferredembodiments, when the dosage form is tampered with and exposed to asmall amount (e.g., less than about 10 ml) of an aqueous liquid (e.g.,water), the dosage form will be unsuitable for injection and/orinhalation. Upon the addition of the aqueous liquid, the tampered dosageform preferably becomes thick and viscous, rendering it unsuitable forinjection. The term “unsuitable for injection” is defined for purposesof the invention to mean that one would have substantial difficultyinjecting the dosage form (e.g., due to pain upon administration ordifficulty pushing the dosage form through a syringe) due to theviscosity imparted on the dosage form, thereby reducing the potentialfor abuse of the therapeutic agent in the dosage form. In certainembodiments, the gelling agent is present in such an amount in thedosage form that attempts at evaporation (by the application of heat) toan aqueous mixture of the dosage form in an effort to produce a higherconcentration of the therapeutic agent, produces a highly viscoussubstance unsuitable for injection. When nasally inhaling the tampereddosage form, the gelling agent can become gel-like upon administrationto the nasal passages, due to the moisture of the mucous membranes. Thisalso makes such formulations aversive to nasal administration, as thegel will stick to the nasal passage and minimize absorption of theabusable substance. Various gelling agents may can be employedincluding, for example, and without limitation, sugars or sugar-derivedalcohols, such as mannitol, sorbitol, and the like, starch and starchderivatives, cellulose derivatives, such as microcrystalline cellulose,sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose, attapulgites, bentonites, dextrins, alginates,carrageenan, gum tragacant, gum acacia, guar gum, xanthan gum, pectin,gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomersand carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethyleneoxide, polyvinyl alcohol, silicon dioxide, surfactants, mixedsurfactant/wetting agent systems, emulsifiers, other polymericmaterials, and mixtures thereof; etc. In certain preferred embodiments,the gelling agent is xanthan gum. In other preferred embodiments, thegelling agent of the invention is pectin. The pectin or pecticsubstances useful for this invention include not only purified orisolated pectates but also crude natural pectin sources, such as apple,citrus or sugar beet residues, which have been subjected, whennecessary, to esterification or de-esterification, e.g., by alkali orenzymes. Preferably, the pectins used in this invention are derived fromcitrus fruits, such as lime, lemon, grapefruit, and orange. With theinclusion of a gelling agent in the dosage form, the gelling agentpreferably imparts a gel-like quality to the dosage form upon tamperingthat spoils or hinders the pleasure of obtaining a rapid high from dueto the gel-like consistency of the tampered dosage form in contact withthe mucous membrane, and in certain embodiments, prevents the abuse ofthe dosage form by minimizing absorption, e.g., in the nasal passages. Agelling agent can be added to the formulation in a ratio of gellingagent to opioid agonist of from about 1:40 to about 40:1 by weight,preferably from about 1:1 to about 30:1 by weight, and more preferablyfrom about 2:1 to about 10:1 by weight of the opioid agonist. In certainother embodiments, the dosage form forms a viscous gel having aviscosity of at least about 10 cP after the dosage form is tampered withby dissolution in an aqueous liquid (from about 0.5 to about 10 ml andpreferably from 1 to about 5 ml). Most preferably, the resulting mixturewill have a viscosity of at least about 60 cP.

The “blocking agent” prevents or substantially prevents the release ofthe antagonist in the gastrointestinal tract for a time period that isgreater than 24 hours, e.g., between 24 and 25 hours, 30 hours, 35hours, 40 hours, 45 hours, 48 hours, 50 hours, 55 hours, 60 hours, 65hours, 70 hours, 72 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95hours, or 100 hours; etc. Preferably, the time period for which therelease of the antagonist is prevented or substantially prevented in thegastrointestinal tract is at least about 48 hours. More preferably, theblocking agent prevents or substantially prevents the release for a timeperiod of at least about 72 hours.

The blocking agent of the present inventive sequestering subunit can bea system comprising a first antagonist-impermeable material and a core.By “antagonist-impermeable material” is meant any material that issubstantially impermeable to the antagonist, such that the antagonist issubstantially not released from the sequestering subunit. The term“substantially impermeable” as used herein does not necessarily implycomplete or 100% impermeability. Rather, there are varying degrees ofimpermeability of which one of ordinary skill in the art recognizes ashaving a potential benefit. In this regard, the antagonist-impermeablematerial substantially prevents or prevents the release of theantagonist to an extent that at least about 80% of the antagonist isprevented from being released from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.Preferably, the antagonist-impermeable material prevents release of atleast about 90% of the antagonist from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.More preferably, the antagonist-impermeable material prevents release ofat least about 95% of the antagonist from the sequestering subunit. Mostpreferably, the antagonist-impermeable material prevents release of atleast about 99% of the antagonist from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.The antagonist-impermeable material prevents or substantially preventsthe release of the antagonist in the gastrointestinal tract for a timeperiod that is greater than 24 hours, and desirably, at least about 48hours. More desirably, the antagonist-impermeable material prevents orsubstantially prevents the release of the adversive agent from thesequestering subunit for a time period of at least about 72 hours.

Preferably, the first antagonist-impermeable material comprises ahydrophobic material, such that the antagonist is not released orsubstantially not released during its transit through thegastrointestinal tract when administered orally as intended, withouthaving been tampered with. Suitable hydrophobic materials for use in theinvention are described herein and set forth below. The hydrophobicmaterial is preferably a pharmaceutically acceptable hydrophobicmaterial.

It is also preferred that the first antagonist-impermeable materialcomprises a polymer insoluble in the gastrointestinal tract. One ofordinary skill in the art appreciates that a polymer that is insolublein the gastrointestinal tract will prevent the release of the antagonistupon ingestion of the sequestering subunit. The polymer may be acellulose or an acrylic polymer. Desirably, the cellulose is selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, andcombinations thereof. Ethylcellulose includes, for example, one that hasan ethoxy content of about 44 to about 55%. Ethylcellulose can be usedin the form of an aqueous dispersion, an alcoholic solution, or asolution in other suitable solvents. The cellulose can have a degree ofsubstitution (D.S.) on the anhydroglucose unit, from greater than zeroand up to 3 inclusive. By “degree of substitution” is meant the averagenumber of hydroxyl groups on the anhydroglucose unit of the cellulosepolymer that are replaced by a substituting group. Representativematerials include a polymer selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate, monocellulosealkanylate, dicellulose alkanylate, tricellulose alkanylate,monocellulose alkenylates, dicellulose alkenylates, tricellulosealkenylates, monocellulose aroylates, dicellulose aroylates, andtricellulose aroylates.

More specific celluloses include cellulose propionate having a D.S. of1.8 and a propyl content of 39.2 to 45 and a hydroxy content of 2.8 to5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxy content of 0.5 to 4.7%; cellulose triacylate havinga D.S. of 2.9 to 3, such as cellulose triacetate, cellulose trivalerate,cellulose trilaurate, cellulose tripatmitate, cellulose trisuccinate,and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate, and coesters of cellulose, such ascellulose acetate butyrate, cellulose acetate octanoate butyrate, andcellulose acetate propionate.

Additional cellulose polymers that may be used to prepare thesequestering subunit include acetaldehyde dimethyl cellulose acetate,cellulose acetate ethylcarbamate, cellulose acetate methycarbamate, andcellulose acetate dimethylaminocellulose acetate.

The acrylic polymer preferably is selected from the group consisting ofmethacrylic polymers, acrylic acid and methacrylic acid copolymers,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), glycidylmethacrylate copolymers, and combinations thereof. An acrylic polymeruseful for preparation of a sequestering subunit of the inventionincludes acrylic resins comprising copolymers synthesized from acrylicand methacrylic acid esters (e.g., the copolymer of acrylic acid loweralkyl ester and methacrylic acid lower alkyl ester) containing about0.02 to about 0.03 mole of a tri (lower alkyl) ammonium group per moleof the acrylic and methacrylic monomer used. An example of a suitableacrylic resin is ammonio methacrylate copolymer NF21, a polymermanufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under theEudragit® trademark. Eudragit® is a water-insoluble copolymer of ethylacrylate (EA), methyl methacrylate (MM) and trimethylammoniumethylmethacrylate chloride (TAM) in which the molar ratio of TAM to theremaining components (EA and MM) is 1:40. Acrylic resins, such asEudragit®, can be used in the form of an aqueous dispersion or as asolution in suitable solvents. Preferred acrylic polymers includecopolymers of acrylic and methacrylic acid esters with a low content inquaternary ammonium groups such as Eudragit® RL PO (Type A) andEudragit® RS PO (Type B; as used herein, “Eudragit® RS”) (as describedthe monographs Ammonia Methacrylate Copolymer Type A Ph. Eur., AmmonioMethacrylate Copolymer Type B Ph. Eur., Ammonio Methacrylate Copolymer,Type A and B USP/NF, and Aminoalkylmethacrylate Copolymer RS JPE).

In another preferred embodiment, the antagonist-impermeable material isselected from the group consisting of polylactic acid, polyglycolicacid, a co-polymer of polylactic acid and polyglycolic acid, andcombinations thereof. In certain other embodiments, the hydrophobicmaterial includes a biodegradable polymer comprising apoly(lactic/glycolic acid) (“PLGA”), a polylactide, a polyglycolide, apolyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes,polysaccharides, proteinaceous polymers, polyesters, polydioxanone,polygluconate, polylactic-acid-polyethylene oxide copolymers,poly(hydroxybutyrate), polyphosphoester or combinations thereof.Preferably, the biodegradable polymer comprises a poly(lactic/glycolicacid), a copolymer of lactic and glycolic acid, having a molecularweight of about 2,000 to about 500,000 daltons. The ratio of lactic acidto glycolic acid is preferably from about 100:1 to about 25:75, with theratio of lactic acid to glycolic acid of about 65:35 being morepreferred.

Poly(lactic/glycolic acid) can be prepared by the procedures set forthin U.S. Pat. No. 4,293,539 (Ludwig et al.), which is incorporated hereinby reference. In brief, Ludwig prepares the copolymer by condensation oflactic acid and glycolic acid in the presence of a readily removablepolymerization catalyst (e.g., a strong ion-exchange resin such as DowexHCR-W2-H). The amount of catalyst is not critical to the polymerization,but typically is from about 0.01 to about 20 parts by weight relative tothe total weight of combined lactic acid and glycolic acid. Thepolymerization reaction can be conducted without solvents at atemperature from about 100° C. to about 250° C. for about 48 to about 96hours, preferably under a reduced pressure to facilitate removal ofwater and by-products. Polylactic/glycolic acid) is then recovered byfiltering the molten reaction mixture in an organic solvent, such asdichloromethane or acetone, and then filtering to remove the catalyst.

Suitable plasticizers for use in the sequestering subunit include, forexample, acetyl triethyl citrate, acetyl tributyl citrate, triethylcitrate, diethyl phthalate, dibutyl phthalate (DBP), acetyltri-N-butylcitrate (ATBC), or dibutyl sebacate, which can be admixed with thepolymer. Other additives such as coloring agents may also be used inmaking the present inventive sequestering subunit.

In certain embodiments, additives may be included in the compositionsthe improve the sequestering characteristics of the sequesteringsubunit. As described below, the ratio of additives or components withrespect to other additives or components may be modified to enhance ordelay improve sequestration of the agent contained within the subunit.Various amounts of a functional additive (i.e., a charge-neutralizingadditive), may be included to vary the release of an antagonist,particularly where a water-soluble core (i.e., a sugar sphere) isutilized. For instance, it has been determined that the inclusion of alow amount of charge-neutralizing additive relative to sequesteringpolymer on a weight-by-weight basis may cause decreased release of theantagonist.

In certain embodiments, a surfactant may serve as a charge-neutralizingadditive. Such neutralization may in certain embodiments reduce theswelling of the sequestering polymer by hydration of positively chargedgroups contained therein. Surfactants (ionic or non-ionic) may also beused in preparing the sequestering subunit. It is preferred that thesurfactant be ionic. Suitable exemplary agents include, for example,alkylaryl sulphonates, alcohol sulphates, sulphosuccinates,sulphosuccinamates, sarcosinates or taurates and others. Additionalexamples include but are not limited to ethoxylated castor oil,benzalkonium chloride, polyglycolyzed glycerides, acetylatedmonoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylenefatty acid esters, polyoxyethylene derivatives, monoglycerides orethoxylated derivatives thereof, diglycerides or polyoxyethylenederivatives thereof, sodium docusate, sodium lauryl sulfate, dioctylsodium sulphosuccinate, sodium lauryl sarcosinate and sodium methylcocoyl taurate, magnesium lauryl sulfate, triethanolamine, cetrimide,sucrose laurate and other sucrose esters, glucose (dextrose) esters,simethicone, ocoxynol, dioctyl sodiumsulfosuceinate, polyglycolyzedglycerides, sodiumdodecylbenzene sulfonate, dialkylsodiumsulfosuccinate, fatty alcohols such as lauryl, cetyl, and steryl,glycerylesters, cholic acid or derivatives thereof, lecithins, andphospholipids. These agents are typically characterized as ionic (i.e.,anionic or cationic) or nonionic. In certain embodiments describedherein, an anionic surfactant such as sodium lauryl sulfate (SLS) ispreferably used (U.S. Pat. No. 5,725,883; U.S. Pat. No. 7,201,920; EP502642A1; Shokri, et al. Pharm. Sci. 2003. The effect of sodium laurylsulphate on the release of diazepam from solid dispersions prepared bycogrinding technique. Wells, et al. Effect of Anionic Surfactants on theRelease of Chlorpheniramine Maleate From an Inert, Heterogeneous Matrix.Drug Development and Industrial Pharmacy 18(2) (1992): 175-186. Rao, etal. “Effect of Sodium Lauryl Sulfate on the Release of Rifampicin fromGuar Gum Matrix.” Indian Journal of Pharmaceutical Science (2000):404-406; Knop, et al. Influence of surfactants of different charge andconcentration on drug release from pellets coated with an aqueousdispersion of quaternary acrylic polymers. STP Pharma Sciences, Vol. 7,No. 6, (1997) 507-512). Other suitable agents are known in the art.

As shown herein, SLS is particularly useful in combination with EudragitRS when the sequestering subunit is built upon a sugar sphere substrate.The inclusion of SLS at less than approximately 6.3% on aweight-to-weight basis relative to the sequestering polymer (i.e.,Eudragit RS) may provide a charge neutralizing function (theoretically20% and 41% neutralization, respectfully), and thereby significantlyslow the release of the active agent encapsulated thereby (i.e., theantagonist naltrexone). Inclusion of more than approximately 6.3% SLSrelative to the sequestering polymer appears to increase release of theantagonist from the sequestering subunit. With respect to SLS used inconjunction with Eudragit® RS, it is preferred that the SLS is presentat approximately 1%, 2%, 3%, 4% or 5%, and typically less than 6% on aw/w basis relative to the sequestering polymer (i.e., Eudragit® RS). Inpreferred embodiments, SLS may be present at approximately 1.6% orapproximately 3.3% relative to the sequestering polymer. As discussedabove, many agents (i.e., surfactants) may substitute for SLS in thecompositions disclosed herein.

Additionally useful agents include those that may physically blockmigration of the antagonist from the subunit and/or enhance thehydrophobicity of the barrier. One exemplary agent is talc, which iscommonly used in pharmaceutical compositions (Pawar et al. Agglomerationof Ibuprofen With Talc by Novel Crystallo-Co-Agglomeration Technique.AAPS PharmSciTech. 2004; 5(4): article 55). As shown in the Examples,talc is especially useful where the sequestering subunit is built upon asugar sphere core. Any form of talc may be used, so long as it does notdetrimentally affect the function of the composition. Most talc resultsfrom the alteration of dolomite (CaMg(CO₃)₂ or magnesite (MgO) in thepresence of excess dissolved silica (SiO₂) or by altering serpentine orquartzite. Talc may be include minerals such as tremolite(CaMg₃(SiO₃)₄), serpentine (3MgO.2SiO₂.2H₂O), anthophyllite(Mg₇.(OH)₂.(Si₄O₁₁)₂), magnesite, mica, chlorite, dolomite, the calciteform of calcium carbonate (CaCO₃), iron oxide, carbon, quartz, and/ormanganese oxide. The presence of such impurities may be acceptable inthe compositions described herein provided the function of the talc ismaintained. It is preferred that that talc be USP grade. As mentionedabove, the function of talc as described herein is to enhance thehydrophobicity and therefore the functionality of the sequesteringpolymer. Many substitutes for talc may be utilized in the compositionsdescribed herein as may be determined by one of skill in the art.

It has been determined that the ratio of talc to sequestering polymermay make a dramatic difference in the functionality of the compositionsdescribed herein. For instance, the Examples described below demonstratethat the talc to sequestering polymer ratio (w/w) is important withrespect to compositions designed to prevent the release of naltrexonetherefrom. It is shown therein that inclusion of an approximatelyequivalent amount (on a weight-by-weight basis) of talc and Eudragit® RSresults in a very low naltrexone release profile. In contrast,significantly lower or higher both a lower (69% w/w) and a higher (151%w/w) talc:Eudragit® RS ratios result in increased release of naltrexonerelease. Thus, where talc and Eudragit® RS are utilized, it is preferredthat talc is present at approximately 75%, 80%, 85%, 90%, 95%, 100%,105%, 110%, 115%, 120% or 125% w/w relative to Eudragit® RS. Asdescribed above, the most beneficial ratio for other additives orcomponents will vary and may be determined using standard experimentalprocedures.

In certain embodiments, such as where a water-soluble core is utilized,it is useful to include agents that may affect the osmotic pressure ofthe composition (i.e., an osmotic pressure regulating agent) (see, ingeneral, WO 2005/046561 A2 and WO 2005/046649 A2 relating toEudramode®). This agent is preferably applied to the Eudragit® RS/talclayer described above. In a pharmaceutical unit comprising asequestering subunit overlayed by an active agent (i.e., acontrolled-release agonist preparation), the osmotic pressure regulatingagent is preferably positioned immediately beneath the active agentlayer. Suitable osmotic pressure regulating agents may include, forinstance, hydroxypropylmethyl cellulose (HPMC) or chloride ions (i.e.,from NaCl), or a combination of HPMC and chloride ions (i.e., fromNaCl). Other ions that may be useful include bromide or iodide. Thecombination of sodium chloride and HPMC may be prepared in water or in amixture of ethanol and water, for instance. HPMC is commonly utilized inpharmaceutical compositions (see, for example, U.S. Pat. Nos. 7,226,620and 7,229,982). In certain embodiments, HPMC may have a molecular weightranging from about 10,000 to about 1,500,000, and typically from about5000 to about 10,000 (low molecular weight HPMC). The specific gravityof HPMC is typically from about 1.19 to about 1.31, with an averagespecific gravity of about 1.26 and a viscosity of about 3600 to 5600.HPMC may be a water-soluble synthetic polymer. Examples of suitable,commercially available hydroxypropyl methylcellulose polymers includeMethocel K100 LV and Methocel K4M (Dow). Other HPMC additives are knownin the art and may be suitable in preparing the compositions describedherein. As shown in the Examples, the inclusion of NaCl (with HPMC) wasfound to have positively affect sequestration of naltrexone by Eudragit®RS. In certain embodiments, it is preferred that the charge-neutralizingadditive (i.e., NaCl) is included at less than approximately 1, 2, 3, 4,5, 6, 7, 8, 9, or 10% on a weight-by-weight basis with respect to thesequestering polymer. In other preferred embodiments, thecharge-neutralizing additive is present at approximately 4% on aweight-by-weight basis with respect to the sequestering polymer.

Thus, in one embodiment, a sequestering subunit built upon a sugarsphere substrate is provided comprising a sequestering polymer (i.e.,Eudragit® RS) in combination with several optimizing agents, includingsodium lauryl sulfate (SLS) as a charge-neutralizing agent to reduceswelling of the film by hydration of the positively charged groups onthe polymer; talc to create a solid impermeable obstacle to naltrexonetransport through the film and as a hydrophobicity-enhancing agent; anda chloride ion (i.e., as NaCl) as an osmotic pressure reducing agent.The ratio of each of the additional ingredients relative to thesequestering polymer was surprisingly found to be important to thefunction of the sequestering subunit. For instance, the Examples providea sequestering subunit including a sequestering polymer and theoptimizing agents SLS at less than 6%, preferably 1-4%, and even morepreferably 1.6% or 3.3% on a w/w basis relative to Eudragit RS; talc inan amount approximately equal to Eudragit® RS (on a w/w basis); and,NaCl present at approximately 4% on a w/w basis relative to Eudragit®RS.

Methods of making any of the sequestering subunits of the invention areknown in the art. See, for example, Remington: The Science and Practiceof Pharmacy, Alfonso R. Genaro (ed), 20^(th) edition, and Example 2 setforth below. The sequestering subunits can be prepared by any suitablemethod to provide, for example, beads, pellets, granules, spheroids, andthe like. Spheroids or beads, coated with an active ingredient can beprepared, for example, by dissolving the active ingredient in water andthen spraying the solution onto a substrate, for example, nu pariel18/20 beads, using a Wurster insert. Optionally, additional ingredientsare also added prior to coating the beads in order to assist the activeingredient in binding to the substrates, and/or to color the solution;etc. The resulting substrate-active material optionally can beovercoated with a barrier material to separate the therapeuticallyactive agent from the next coat of material, e.g., release-retarding orsequestering material. Preferably, the barrier material is a materialcomprising hydroxypropyl methylcellulose. However, any film-former knownin the art can be used. Preferably, the barrier material does not affectthe dissolution rate of the final product.

Pellets comprising an active ingredient can be prepared, for example, bya melt pelletization technique. Typical of such techniques is when theactive ingredient in finely divided form is combined with a binder (alsoin particulate form) and other optional inert ingredients, andthereafter the mixture is pelletized, e.g., by mechanically working themixture in a high shear mixer to form the pellets (e.g., pellets,granules, spheres, beads; etc., collectively referred to herein as“pellets”). Thereafter, the pellets can be sieved in order to obtainpellets of the requisite size. The binder material is preferably inparticulate form and has a melting point above about 40° C. Suitablebinder substances include, for example, hydrogenated castor oil,hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols,fatty acid esters, fatty acid glycerides, and the like.

The diameter of the extruder aperture or exit port also can be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular;etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine; etc.

The melt-extruded multiparticulate system can be, for example, in theform of granules, spheroids, pellets, or the like, depending upon theextruder exit orifice. The terms “melt-extruded multiparticulate(s)” and“melt-extruded multiparticulate system(s)” and “melt-extruded particles”are used interchangeably herein and include a plurality of subunits,preferably within a range of similar size and/or shape. Themelt-extruded multiparticulates are preferably in a range of from about0.1 to about 12 mm in length and have a diameter of from about 0.1 toabout 5 mm. In addition, the melt-extruded multiparticulates can be anygeometrical shape within this size range. Alternatively, the extrudatecan simply be cut into desired lengths and divided into unit doses ofthe therapeutically active agent without the need of a spheronizationstep.

The substrate also can be prepared via a granulation technique.Generally, melt-granulation techniques involve melting a normally solidhydrophobic material, e.g., a wax, and incorporating an activeingredient therein. To obtain a sustained-release dosage form, it can benecessary to incorporate an additional hydrophobic material.

A coating composition can be applied onto a substrate by spraying itonto the substrate using any suitable spray equipment. For example, aWurster fluidized-bed system can be used in which an air flow fromunderneath, fluidizes the coated material and effects drying, while theinsoluble polymer coating is sprayed on. The thickness of the coatingwill depend on the characteristics of the particular coatingcomposition, and can be determined by using routine experimentation.

Any manner of preparing a subunit can be employed. By way of example, asubunit in the form of a pellet or the like can be prepared byco-extruding a material comprising the opioid agonist and a materialcomprising the opioid antagonist and/or antagonist in sequestered form.Optionally, the opioid agonist composition can cover, e.g., overcoat,the material comprising the antagonist and/or antagonist in sequesteredform. A bead, for example, can be prepared by coating a substratecomprising an opioid antagonist and/or an antagonist in sequestered formwith a solution comprising an opioid agonist.

The sequestering subunits of the invention are particularly well-suitedfor use in compositions comprising the sequestering subunit and atherapeutic agent in releasable form. In this regard, the invention alsoprovides a composition comprising any of the sequestering subunits ofthe invention and a therapeutic agent in releasable form. By “releasableform” is meant to include immediate release, intermediate release, andsustained-release forms. The therapeutic agent can be formulated toprovide immediate release of the therapeutic agent. In preferredembodiments, the composition provides sustained-release of thetherapeutic agent.

The therapeutic agent applied upon the sequestering subunit may be anymedicament. The therapeutic agent of the present inventive compositionscan be any medicinal agent used for the treatment of a condition ordisease, a pharmaceutically acceptable salt thereof, or an analogue ofeither of the foregoing. The therapeutic agent can be, for example, ananalgesic (e.g., an opioid agonist, aspirin, acetaminophen,non-steroidal anti-inflammatory drugs (“NSAIDS”), N-methyl-D-aspartate(“NMDA”) receptor antagonists, cyclooxygenase-II inhibitors (“COX-IIinhibitors”), and glycine receptor antagonists), an antibacterial agent,an anti-viral agent, an anti-microbial agent, anti-infective agent, achemotherapeutic, an immunosuppressant agent, an antitussive, anexpectorant, a decongestant, an antihistamine drugs, a decongestant,antihistamine drugs, and the like. Preferably, the therapeutic agent isone that is addictive (physically and/or psychologically) upon repeateduse and typically leads to abuse of the therapeutic agent. In thisregard, the therapeutic agent can be any opioid agonist as discussedherein.

The therapeutic agent can be an opioid agonist. By “opioid” is meant toinclude a drug, hormone, or other chemical or biological substance,natural or synthetic, having a sedative, narcotic, or otherwise similareffect(s) to those containing opium or its natural or syntheticderivatives. By “opioid agonist,” sometimes used herein interchangeablywith terms “opioid” and “opioid analgesic,” is meant to include one ormore opioid agonists, either alone or in combination, and is furthermeant to include the base of the opioid, mixed or combinedagonist-antagonists, partial agonists, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers thereof, esters thereof, andcombinations thereof.

Opioid agonists include, for example, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydroetorphine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl,heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenazocine,phenomorphan, phenoperidine, piminodine, piritramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol;tilidine, derivatives or complexes thereof, pharmaceutically acceptablesalts thereof, and combinations thereof. Preferably, the opioid agonistis selected from the group consisting of hydrocodone, hydromorphone,oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine,buprenorphine, derivatives or complexes thereof, pharmaceuticallyacceptable salts thereof, and combinations thereof. Most preferably, theopioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. Ina preferred embodiment, the opioid agonist comprises oxycodone orhydrocodone and is present in the dosage form in an amount of about 15to about 45 mg, and the opioid antagonist comprises naltrexone and ispresent in the dosage form in an amount of about 0.5 to about 5 mg.

Equianalgesic doses of these opioids, in comparison to a 15 mg dose ofhydrocodone, are set forth in Table 1 below:

TABLE I Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple nervous system and gastrointestinal actions. Chemically,hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one, and is alsoknown as dihydrocodeinone. Like other opioids, hydrocodone can behabit-forming and can produce drug dependence of the morphine type. Likeother opium derivatives, excess doses of hydrocodone will depressrespiration.

Oral hydrocodone is also available in Europe (e.g., Belgium, Germany,Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussiveagent. A parenteral formulation is also available in Germany as anantitussive agent. For use as an analgesic, hydrocodone bitartrate iscommonly available in the United States only as a fixed combination withnon-opiate drugs (e.g., ibuprofen, acetaminophen, aspirin; etc.) forrelief of moderate to moderately severe pain.

A common dosage form of hydrocodone is in combination with acetaminophenand is commercially available, for example, as Lortab® in the UnitedStates from UCB Pharma, Inc. (Brussels, Belgium), as 2.5/500 mg, 5/500mg, 7.5/500 mg and 10/500 mg hydrocodone/acetaminophen tablets. Tabletsare also available in the ratio of 7.5 mg hydrocodone bitartrate and 650mg acetaminophen and a 7.5 mg hydrocodone bitartrate and 750 mgacetaminophen. Hydrocodone, in combination with aspirin, is given in anoral dosage form to adults generally in 1-2 tablets every 4-6 hours asneeded to alleviate pain. The tablet form is 5 mg hydrocodone bitartrateand 224 mg aspirin with 32 mg caffeine; or 5 mg hydrocodone bitartrateand 500 mg aspirin. Another formulation comprises hydrocodone bitartrateand ibuprofen. Vicoprofen®, commercially available in the U.S. fromKnoll Laboratories (Mount Olive, N.J.), is a tablet containing 7.5 mghydrocodone bitartrate and 200 mg ibuprofen. The invention iscontemplated to encompass all such formulations, with the inclusion ofthe opioid antagonist and/or antagonist in sequestered form as part of asubunit comprising an opioid agonist.

Oxycodone, chemically known as4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.Oxycodone is commercially available in the United States, e.g., asOxycotin® from Purdue Pharma L.P. (Stamford, Conn.), ascontrolled-release tablets for oral administration containing 10 mg, 20mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxyIR™, also fromPurdue Pharma L.P., as immediate-release capsules containing 5 mgoxycodone hydrochloride. The invention is contemplated to encompass allsuch formulations, with the inclusion of an opioid antagonist and/orantagonist in sequestered form as part of a subunit comprising an opioidagonist.

Oral hydromorphone is commercially available in the United States, e.g.,as Dilaudid® from Abbott Laboratories (Chicago, Ill.). Oral morphine iscommercially available in the United States, e.g., as Kadian® fromFaulding Laboratories (Piscataway, N.J.).

Exemplary NSAIDS include ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam or isoxicam, and the like. Useful dosages of thesedrugs are well-known. Exemplary NMDA receptor medicaments includemorphinans, such as dexotromethorphan or dextrophan, ketamine,d-methadone, and pharmaceutically acceptable salts thereof, andencompass drugs that block a major intracellular consequence ofNMDA-receptor activation, e.g., a ganglioside, such as(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics, such as morphine, codeine;etc., in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer et al.),both of which are incorporated herein by reference, and to treat chronicpain in U.S. Pat. No. 5,502,058 (Mayer et al.), incorporated herein byreference. The NMDA agonist can be included alone or in combination witha local anesthetic, such as lidocaine, as described in these patents byMayer et al.

COX-2 inhibitors have been reported in the art, and many chemicalcompounds are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944 and5,130,311, all of which are incorporated herein by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2-naphthylacetic acid(6-NMA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614, or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day have been shown to betherapeutically effective in combination with an opioid analgesic.Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2inhibitor can be administered in combination with an opioid analgesic.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber et al.), which is incorporated herein byreference.

In embodiments in which the opioid agonist comprises hydrocodone, thesustained-release oral dosage forms can include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. Insustained-release oral dosage forms where hydromorphone is thetherapeutically active opioid, it is included in an amount from about 2mg to about 64 mg hydromorphone hydrochloride. In another embodiment,the opioid agonist comprises morphine, and the sustained-release oraldosage forms of the invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid agonistcomprises oxycodone and the sustained-release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. In certain preferredembodiments, the sustained-release oral dosage forms include from about20 mg to about 30 mg oxycodone. Controlled release oxycodoneformulations are known in the art. The following documents describevarious controlled-release oxycodone formulations suitable for use inthe invention described herein, and processes for their manufacture:U.S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656,295, which areincorporated herein by reference. The opioid agonist can comprisetramadol and the sustained-release oral dosage forms can include fromabout 25 mg to 800 mg tramadol per dosage unit.

The therapeutic agent in sustained-release form is preferably a particleof therapeutic agent that is combined with a release-retarding orsequestering material. The release-retarding or sequestering material ispreferably a material that permits release of the therapeutic agent at asustained rate in an aqueous medium. The release-retarding orsequestering material can be selectively chosen so as to achieve, incombination with the other stated properties, a desired in vitro releaserate.

In a preferred embodiment, the oral dosage form of the invention can beformulated to provide for an increased duration of therapeutic actionallowing once-daily dosing. In general, a release-retarding orsequestering material is used to provide the increased duration oftherapeutic action. Preferably, the once-daily dosing is provided by thedosage forms and methods described in U.S. patent application Ser. No.______ (unknown) to Boehm, entitled “Sustained-Release OpioidFormulations and Method of Use,” filed on Sep. 22, 2003, andincorporated herein by reference.

Preferred release-retarding or sequestering materials include acrylicpolymers, alkylcelluloses, shellac, zein, hydrogenated vegetable oil,hydrogenated castor oil, and combinations thereof. In certain preferredembodiments, the release-retarding or sequestering material is apharmaceutically acceptable acrylic polymer, including acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acidanhydride), methyl methacrylate, polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, and glycidyl methacrylate copolymers. In certain preferredembodiments, the acrylic polymer comprises one or more ammoniomethacrylate copolymers. Ammonio methacrylate copolymers are well-knownin the art, and are described in NF21, the 21^(st) edition of theNational Formulary, published by the United States PharmacopeialConvention Inc. (Rockville, Md.), as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. In other preferred embodiments; the release-retardingor sequestering material is an alkyl cellulosic material, such asethylcellulose. Those skilled in the art will appreciate that othercellulosic polymers, including other alkyl cellulosic polymers, can besubstituted for part or all of the ethylcellulose.

Release-modifying agents, which affect the release properties of therelease-retarding or sequestering material, also can be used. In apreferred embodiment, the release-modifying agent functions as apore-former. The pore-former can be organic or inorganic, and includematerials that can be dissolved, extracted or leached from the coatingin the environment of use. The pore-former can comprise one or morehydrophilic polymers, such as hydroxypropylmethylcellulose. In certainpreferred embodiments, the release-modifying agent is selected fromhydroxypropylmethylcellulose, lactose, metal stearates, and combinationsthereof.

The release-retarding or sequestering material can also include anerosion-promoting agent, such as starch and gums; a release-modifyingagent useful for making microporous lamina in the environment of use,such as polycarbonates comprised of linear polyesters of carbonic acidin which carbonate groups reoccur in the polymer chain; and/or asemi-permeable polymer.

The release-retarding or sequestering material can also include an exitmeans comprising at least one passageway, orifice, or the like. Thepassageway can be formed by such methods as those disclosed in U.S. Pat.Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864, which areincorporated herein by reference. The passageway can have any shape,such as round, triangular, square, elliptical, irregular; etc.

In certain embodiments, the therapeutic agent in sustained-release formcan include a plurality of substrates comprising the active ingredient,which substrates are coated with a sustained-release coating comprisinga release-retarding or sequestering material.

The sustained-release preparations of the invention can be made inconjunction with any multiparticulate system, such as beads,ion-exchange resin beads, spheroids, microspheres, seeds, pellets,granules, and other multiparticulate systems in order to obtain adesired sustained-release of the therapeutic agent. The multiparticulatesystem can be presented in a capsule or in any other suitable unitdosage form.

In certain preferred embodiments, more than one multiparticulate systemcan be used, each exhibiting different characteristics, such as pHdependence of release, time for release in various media (e.g., acid,base, simulated intestinal fluid), release in vivo, size andcomposition.

To obtain a sustained-release of the therapeutic agent in a mannersufficient to provide a therapeutic effect for the sustained durations,the therapeutic agent can be coated with an amount of release-retardingor sequestering material sufficient to obtain a weight gain level fromabout 2 to about 30%, although the coat can be greater or lesserdepending upon the physical properties of the particular therapeuticagent utilized and the desired release rate, among other things.Moreover, there can be more than one release-retarding or sequesteringmaterial used in the coat, as well as various other pharmaceuticalexcipients.

Solvents typically used for the release-retarding or sequesteringmaterial include pharmaceutically acceptable solvents, such as water,methanol, ethanol, methylene chloride and combinations thereof.

In certain embodiments of the invention, the release-retarding orsequestering material is in the form of a coating comprising an aqueousdispersion of a hydrophobic polymer. The inclusion of an effectiveamount of a plasticizer in the aqueous dispersion of hydrophobic polymerwill further improve the physical properties of the film. For example,because ethylcellulose has a relatively high glass transitiontemperature and does not form flexible films under normal coatingconditions, it is necessary to plasticize the ethylcellulose beforeusing the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentrations of the plasticizer, however,can be determined by routine experimentation.

Examples of plasticizers for ethylcellulose and other celluloses includedibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate,and triacetin, although it is possible that other plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil; etc.) can beused. A plasticizer that is not leached into the aqueous phase such asDBS is preferred.

Examples of plasticizers for the acrylic polymers include citric acidesters, such as triethyl citrate NF21, tributyl citrate, dibutylphthalate (DBP), acetyltri-N-butyl citrate (ATBC), and possibly1,2-propylene glycol, polyethylene glycols, propylene glycol, diethylphthalate, castor oil, and triacetin, although it is possible that otherplasticizers (such as acetylated monoglycerides, phthalate esters,castor oil; etc.) can be used.

The sustained-release profile of drug release in the formulations of theinvention (either in vivo or in vitro) can be altered, for example, byusing more than one release-retarding or sequestering material, varyingthe thickness of the release-retarding or sequestering material,changing the particular release-retarding or sequestering material used,altering the relative amounts of release-retarding or sequesteringmaterial, altering the manner in which the plasticizer is added (e.g.,when the sustained-release coating is derived from an aqueous dispersionof hydrophobic polymer), by varying the amount of plasticizer relativeto retardant material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture; etc.

In certain other embodiments, the oral dosage form can utilize amultiparticulate sustained-release matrix. In certain embodiments, thesustained-release matrix comprises a hydrophilic and/or hydrophobicpolymer, such as gums, cellulose ethers, acrylic resins andprotein-derived materials. Of these polymers, the cellulose ethers,specifically hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. The oral dosage form can contain between about 1% and about80% (by weight) of at least one hydrophilic or hydrophobic polymer.

The hydrophobic material is preferably selected from the groupconsisting of alkylcellulose, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. Preferably, the hydrophobic materialis a pharmaceutically acceptable acrylic polymer, including acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial can also include hydrooxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophobic trends. Preferably, the hydrophobic material hasa melting point from about 30° C. to about 200° C., more preferably fromabout 45° C. to about 90° C. The hydrophobic material can includeneutral or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicacid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include beeswax, glycowax, castorwax, carnauba wax and wax-like substances, e.g., material normally solidat room temperature and having a melting point of from about 30° C. toabout 100° C.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably a natural or synthetic wax, afatty acid, a fatty alcohol, or mixtures thereof. Examples includebeeswax, carnauba wax, stearic acid and stearyl alcohol.

In other embodiments, the sustained-release matrix comprises digestible,long-chain (e.g., C₈-C₅₀, preferably C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between about 25° C. and about90° C. are preferred. Of these long-chain hydrocarbon materials, fatty(aliphatic) alcohols are preferred. The oral dosage form can contain upto about 60% (by weight) of at least one digestible, long-chainhydrocarbon. Further, the sustained-release matrix can contain up to 60%(by weight) of at least one polyalkylene glycol.

In a preferred embodiment, the matrix comprises at least onewater-soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁-C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, preferably, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the oral dosageform will be determined, amongst other things, by the precise rate ofopioid release required. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined by theprecise rate of opioid release required. However, it will also depend onwhether the at least one polyalkylene glycol is absent from the oraldosage form.

In certain embodiments, a spheronizing agent, together with the activeingredient, can be spheronized to form spheroids. Microcrystallinecellulose and hydrous lactose impalpable are examples of such agents.Additionally (or alternatively), the spheroids can contain awater-insoluble polymer, preferably an acrylic polymer, an acryliccopolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose. In such embodiments, the sustained-release coating willgenerally include a water-insoluble material such as (a) a wax, eitheralone or in admixture with a fatty alcohol, or (b) shellac or zein.

The sustained-release unit can be prepared by any suitable method. Forexample, a plasticized aqueous dispersion of the release-retarding orsequestering material can be applied onto the subunit comprising theopioid agonist. A sufficient amount of the aqueous dispersion ofrelease-retarding or sequestering material to obtain a predeterminedsustained-release of the opioid agonist when the coated substrate isexposed to aqueous solutions, e.g., gastric fluid, is preferablyapplied, taking into account the physical characteristics of the opioidagonist, the manner of incorporation of the plasticizer; etc.Optionally, a further overcoat of a film-former, such as Opadry(Colorcon, West Point, Va.), can be applied after coating with therelease-retarding or sequestering material.

The subunit can be cured in order to obtain a stabilized release rate ofthe therapeutic agent. In embodiments employing an acrylic coating, astabilized product can be preferably obtained by subjecting the subunitto oven curing at a temperature above the glass transition temperatureof the plasticized acrylic polymer for the required time period. Theoptimum temperature and time for the particular formulation can bedetermined by routine experimentation.

Once prepared, the subunit can be combined with at least one additionalsubunit and, optionally, other excipients or drugs to provide an oraldosage form. In addition to the above ingredients, a sustained-releasematrix also can contain suitable quantities of other materials, e.g.,diluents, lubricants, binders, granulating aids, colorants, flavorantsand glidants that are conventional in the pharmaceutical art.

Optionally and preferably, the mechanical fragility of any of thesequestering subunits described herein is the same as the mechanicalfragility of the therapeutic agent in releasable form. In this regard,tampering with the composition of the invention in a manner to obtainthe therapeutic agent will result in the destruction of the sequesteringsubunit, such that the antagonist is released and mixed in with thetherapeutic agent. Consequently, the antagonist cannot be separated fromthe therapeutic agent, and the therapeutic agent cannot be administeredin the absence of the antagonist. Methods of assaying the mechanicalfragility of the sequestering subunit and of a therapeutic agent areknown in the art.

The composition of the invention can be in any suitable dosage form orformulation, (see, e.g., Pharmaceutics and Pharmacy Practice, J. B.Lippincott Company, Philadelphia, Pa., Banker and Chalmers, eds., pages238-250 (1982)).

Pharmaceutically acceptable salts of the antagonist or agonist agentsdiscussed herein include metal salts, such as sodium salt, potassiumsalt, cesium salt, and the like; alkaline earth metals, such as calciumsalt, magnesium salt, and the like; organic amine salts, such astriethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, and the like; inorganic acid salts,such as hydrochloride, hydrobromide, sulfate, phosphate, and the like;organic acid salts, such as formate, acetate, trifluoroacetate, maleate,tartrate, and the like; sulfonates, such as methanesulfonate,benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts,such as arginate, asparginate, glutamate, and the like. Formulationssuitable for oral administration can consist of (a) liquid solutions,such as an effective amount of the inhibitor dissolved in diluents, suchas water, saline, or orange juice; (b) capsules, sachets, tablets,lozenges, and troches, each containing a predetermined amount of theactive ingredient, as solids or granules; (c) powders; (d) suspensionsin an appropriate liquid; and (e) suitable emulsions. Liquidformulations may include diluents, such as water and alcohols, forexample, ethanol, benzyl alcohol, and the polyethylene alcohols, eitherwith or without the addition of a pharmaceutically acceptablesurfactant. Capsule forms can be of the ordinary hard- or soft-shelledgelatin type containing, for example, surfactants, lubricants, and inertfillers, such as lactose, sucrose, calcium phosphate, and corn starch.Tablet forms can include one or more of lactose, sucrose, mannitol, cornstarch, potato starch, alginic acid, microcrystallize cellulose, acacia,gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium,talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid,and other excipients, colorants, diluents, buffering agents,disintegrating agents, moistening agents, preservatives, flavoringagents, and pharmacologically compatible excipients. Lozenge forms cancomprise the active ingredient in a flavor, usually sucrose and acaciaor tragacanth, as well as pastilles comprising the active ingredient inan inert base, such as gelatin and glycerin, or sucrose and acacia,emulsions, gels, and the like containing, in addition to the activeingredient, such excipients as are known in the art.

One of ordinary skill in the art will readily appreciate that thecompositions of the invention can be modified in any number of ways,such that the therapeutic efficacy of the composition is increasedthrough the modification. For instance, the therapeutic agent orsequestering subunit could be conjugated either directly or indirectlythrough a linker to a targeting moiety. The practice of conjugatingtherapeutic agents or sequestering subunits to targeting moieties isknown in the art. See, for instance, Wadwa et al., J. Drug Targeting 3:111 (1995), and U.S. Pat. No. 5,087,616. The term “targeting moiety” asused herein, refers to any molecule or agent that specificallyrecognizes and binds to a cell-surface receptor, such that the targetingmoiety directs the delivery of the therapeutic agent or sequesteringsubunit to a population of cells on which the receptor is expressed.Targeting moieties include, but are not limited to, antibodies, orfragments thereof, peptides, hormones, growth factors, cytokines, andany other naturally- or non-naturally-existing ligands, which bind tocell-surface receptors. The term “linker” as used herein, refers to anyagent or molecule that bridges the therapeutic agent or sequesteringsubunit to the targeting moiety. One of ordinary skill in the artrecognizes that sites on the therapeutic agent or sequestering subunit,which are not necessary for the function of the agent or sequesteringsubunit, are ideal sites for attaching a linker and/or a targetingmoiety, provided that the linker and/or targeting moiety, once attachedto the agent or sequestering subunit, do(es) not interfere with thefunction of the therapeutic agent or sequestering subunit.

With respect to the present inventive compositions, the composition ispreferably an oral dosage form. By “oral dosage form” is meant toinclude a unit dosage form prescribed or intended for oraladministration comprising subunits. Desirably, the composition comprisesthe sequestering subunit coated with the therapeutic agent in releasableform, thereby forming a composite subunit comprising the sequesteringsubunit and the therapeutic agent. Accordingly, the invention furtherprovides a capsule suitable for oral administration comprising aplurality of such composite subunits.

Alternatively, the oral dosage form can comprise any of the sequesteringsubunits of the invention in combination with a therapeutic agentsubunit, wherein the therapeutic agent subunit comprises the therapeuticagent in releasable form. In this respect, the invention provides acapsule suitable for oral administration comprising a plurality ofsequestering subunits of the invention and a plurality of therapeuticsubunits, each of which comprises a therapeutic agent in releasableform.

The invention further provides tablets comprising a sequestering subunitof the invention and a therapeutic agent in releasable form. Forinstance, the invention provides a tablet suitable for oraladministration comprising a first layer comprising any of thesequestering subunits of the invention and a second layer comprisingtherapeutic agent in releasable form, wherein the first layer is coatedwith the second layer. The first layer can comprise a plurality ofsequestering subunits. Alternatively, the first layer can be or canconsist of a single sequestering subunit. The therapeutic agent inreleasable form can be in the form of a therapeutic agent subunit andthe second layer can comprise a plurality of therapeutic subunits.Alternatively, the second layer can comprise a single substantiallyhomogeneous layer comprising the therapeutic agent in releasable form.

When the blocking agent is a system comprising a firstantagonist-impermeable material and a core, the sequestering subunit canbe in one of several different forms. For example, the system canfurther comprise a second antagonist-impermeable material, in which casethe sequestering unit comprises an antagonist, a firstantagonist-impermeable material, a second antagonist-impermeablematerial, and a core. In this instance, the core is coated with thefirst antagonist-impermeable material, which, in turn, is coated withthe antagonist, which, in turn, is coated with the secondantagonist-impermeable material. The first antagonist-impermeablematerial and second antagonist-impermeable material substantiallyprevent release of the antagonist from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.In some instances, it is preferable that the firstantagonist-impermeable material is the same as the secondantagonist-impermeable material. In other instances, the firstantagonist-impermeable material is different from the secondantagonist-impermeable material. It is within the skill of the ordinaryartisan to determine whether or not the first and secondantagonist-impermeable materials should be the same or different.Factors that influence the decision as to whether the first and secondantagonist-impermeable materials should be the same or different caninclude whether a layer to be placed over the antagonist-impermeablematerial requires certain properties to prevent dissolving part or allof the antagonist-impermeable layer when applying the next layer orproperties to promote adhesion of a layer to be applied over theantagonist-impermeable layer.

Alternatively, the antagonist can be incorporated into the core, and thecore is coated with the first antagonist-impermeable material. In thiscase, the invention provides a sequestering subunit comprising anantagonist, a core and a first antagonist-impermeable material, whereinthe antagonist is incorporated into the core and the core is coated withthe first antagonist-impermeable material, and wherein the firstantagonist-impermeable material substantially prevents release of theantagonist from the sequestering subunit in the gastrointestinal tractfor a time period that is greater than 24 hours. By “incorporate” andwords stemming therefrom, as used herein is meant to include any meansof incorporation, e.g., homogeneous dispersion of the antagonistthroughout the core, a single layer of the antagonist coated on top of acore, or a multi-layer system of the antagonist, which comprises thecore.

In another alternative embodiment, the core comprises a water-insolublematerial, and the core is coated with the antagonist, which, in turn, iscoated with the first antagonist-impermeable material. In this case, theinvention further provides a sequestering subunit comprising anantagonist, a first antagonist-impermeable material, and a core, whichcomprises a water-insoluble material, wherein the core is coated withthe antagonist, which, in turn, is coated with the firstantagonist-impermeable material, and wherein the firstantagonist-impermeable material substantially prevents release of theantagonist from the sequestering subunit in the gastrointestinal tractfor a time period that is greater than 24 hours. The term“water-insoluble material” as used herein means any material that issubstantially water-insoluble. The term “substantially water-insoluble”does not necessarily refer to complete or 100% water-insolubility.Rather, there are varying degrees of water insolubility of which one ofordinary skill in the art recognizes as having a potential benefit.Preferred water-insoluble materials include, for example,microcrystalline cellulose, a calcium salt, and a wax. Calcium saltsinclude, but are not limited to, a calcium phosphate (e.g.,hydroxyapatite, apatite; etc.), calcium carbonate, calcium sulfate,calcium stearate, and the like. Waxes include, for example, carnuba wax,beeswax, petroleum wax, candelilla wax, and the like.

In one embodiment, the sequestering subunit includes an antagonist and aseal coat where the seal coat forms a layer physically separating theantagonist within the sequestering subunit from the agonist which islayered upon the sequestering subunit. In one embodiment, the seal coatcomprises one or more of an osmotic pressure regulating agent, acharge-neutralizing additive, a sequestering polymerhydrophobicity-enhancing additive, and a first sequestering polymer(each having been described above). In such embodiments, it is preferredthat the osmotic pressure regulating agent, charge-neutralizingadditive, and/or sequestering polymer hydrophobicity-enhancing additive,respectively where present, are present in proportion to the firstsequestering polymer such that no more than 10% of the antagonist isreleased from the intact dosage form. Where an opioid antagonist is usedin the sequestering subunit and the intact dosage form includes anopioid agonist, it is preferred that ratio of the osmotic pressureregulating agent, charge-neutralizing additive, and/or sequesteringpolymer hydrophobicity-enhancing additive, respectively where present,in relation to the first sequestering polymer is such that thephysiological effect of the opioid agonist is not diminished when thecomposition is in its intact dosage form or during the normal coursedigestion in the patient. Release may be determined as described aboveusing the USP paddle method (optionally using a buffer containing asurfactant such as Triton X-100) or measured from plasma afteradministration to a patient in the fed or non-fed state. In oneembodiment, plasma naltrexone levels are determined; in others, plasma6-beta naltrexol levels are determined. Standard tests may be utilizedto ascertain the antagonist's effect on agonist function (i.e.,reduction of pain).

The sequestering subunit of the invention can have a blocking agent thatis a tether to which the antagonist is attached. The term “tether” asused herein refers to any means by which the antagonist is tethered orattached to the interior of the sequestering subunit, such that theantagonist is not released, unless the sequestering subunit is tamperedwith. In this instance, a tether-antagonist complex is formed. Thecomplex is coated with a tether-impermeable material, therebysubstantially preventing release of the antagonist from the subunit. Theterm “tether-impermeable material” as used herein refers to any materialthat substantially prevents or prevents the tether from permeatingthrough the material. The tether preferably is an ion exchange resinbead.

The invention further provides a tablet suitable for oral administrationcomprising a single layer comprising a therapeutic agent in releasableform and a plurality of any of the sequestering subunits of theinvention dispersed throughout the layer of the therapeutic agent inreleasable form. The invention also provides a tablet in which thetherapeutic agent in releasable form is in the form of a therapeuticagent subunit and the tablet comprises an at least substantiallyhomogeneous mixture of a plurality of sequestering subunits and aplurality of subunits comprising the therapeutic agent.

In preferred embodiments, oral dosage forms are prepared to include aneffective amount of melt-extruded subunits in the form of multiparticleswithin a capsule. For example, a plurality of the melt-extrudedmultiparticulates can be placed in a gelatin capsule in an amountsufficient to provide an effective release dose when ingested andcontacted by gastric fluid.

In another preferred embodiment, the subunits, e.g., in the form ofmultiparticulates, can be compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Aurther Osol., editor), 1553-1593 (1980),which is incorporated herein by reference. Excipients in tabletformulation can include, for example, an inert diluent such as lactose,granulating and disintegrating agents, such as cornstarch, bindingagents, such as starch, and lubricating agents, such as magnesiumstearate. In yet another preferred embodiment, the subunits are addedduring the extrusion process and the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch et al.), whichis incorporated herein by reference.

Optionally, the sustained-release, melt-extruded, multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained-release coating, such as the sustained-releasecoatings described herein. Such coatings are particularly useful whenthe subunit comprises an opioid agonist in releasable form, but not insustained-release form. The coatings preferably include a sufficientamount of a hydrophobic material to obtain a weight gain level formabout 2 to about 30 percent, although the overcoat can be greater,depending upon the physical properties of the particular opioidanalgesic utilized and the desired release rate, among other things.

The melt-extruded dosage forms can further include combinations ofmelt-extruded multiparticulates containing one or more of thetherapeutically active agents before being encapsulated. Furthermore,the dosage forms can also include an amount of an immediate releasetherapeutic agent for prompt therapeutic effect. The immediate releasetherapeutic agent can be incorporated or coated on the surface of thesubunits after preparation of the dosage forms (e.g., controlled-releasecoating or matrix-based). The dosage forms can also contain acombination of controlled-release beads and matrix multiparticulates toachieve a desired effect.

The sustained-release formulations preferably slowly release thetherapeutic agent, e.g., when ingested and exposed to gastric fluids,and then to intestinal fluids. The sustained-release profile of themelt-extruded formulations can be altered, for example, by varying theamount of retardant, e.g., hydrophobic material, by varying the amountof plasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture; etc.

In other embodiments, the melt-extruded material is prepared without theinclusion of the subunits, which are added thereafter to the extrudate.Such formulations can have the subunits and other drugs blended togetherwith the extruded matrix material, and then the mixture is tableted inorder to provide a slow release of the therapeutic agent or other drugs.Such formulations can be particularly advantageous, for example, whenthe therapeutically active agent included in the formulation issensitive to temperatures needed for softening the hydrophobic materialand/or the retardant material.

In certain embodiments, the release of the antagonist of thesequestering subunit or composition is expressed in terms of a ratio ofthe release achieved after tampering, e.g., by crushing or chewing,relative to the amount released from the intact formulation. The ratiois, therefore, expressed as Crushed:Whole, and it is desired that thisratio have a numerical range of at least about 4:1 or greater (e.g.,crushed release within 1 hour/intact release in 24 hours). In certainembodiments, the ratio of the therapeutic agent and the antagonist,present in the sequestering subunit, is about 1:1 to about 50:1 byweight, preferably about 1:1 to about 20:1 by weight or 15:1 to about30:1 by weight. The weight ratio of the therapeutic agent to antagonistrefers to the weight of the active ingredients. Thus, for example, theweight of the therapeutic agent excludes the weight of the coating,matrix, or other component that renders the antagonist sequestered, orother possible excipients associated with the antagonist particles. Incertain preferred embodiments, the ratio is about 1:1 to about 10:1 byweight. Because in certain embodiments the antagonist is in asequestered from, the amount of such antagonist within the dosage formcan be varied more widely than the therapeutic agent/antagonistcombination dosage forms, where both are available for release uponadministration, as the formulation does not depend on differentialmetabolism or hepatic clearance for proper functioning. For safetyreasons, the amount of the antagonist present in a substantiallynon-releasable form is selected as not to be harmful to humans, even iffully released under conditions of tampering.

Thus, in certain embodiments, a pharmaceutical composition comprising anantagonist in direct contact with a seal coat, an agonist in directcontact with the seal coat and a sequestering polymer but not theantagonist, wherein the antagonist and agonist are present within asingle multilayer pharmaceutical unit, is provided. In others,pharmaceutical compositions comprising a pharmaceutical dosing unitconsisting essentially of a multiple layer bead comprising an antagonistand an agonist that are not in direct contact with one another areprovided. In yet others, pharmaceutical composition comprising aplurality of pharmaceutically active units wherein each unit comprisesan antagonist, an agonist, a seal coat, and a sequestering polymerwherein the antagonist and the agonist are not in direct contact withone another. In still others, pharmaceutical compositions comprising apharmaceutically inert support material such as a sugar sphere, anantagonist in direct contact with the support material, a seal coat indirect contact with the antagonist and an agonist, and a sequesteringpolymer in direct contact with the agonist are provided. In preferredembodiments, multiple layer pharmaceutical compositions comprising anagonist and an antagonist within distinct layers of the composition,wherein at least 90-95% of the antagonist is sequestered for at least 24hours following administration to a human being are provided. In aparticularly preferred embodiment, a pharmaceutical compositioncomprising naltrexone within a sequestering subunit and morphine incontact with the subunit but not the naltrexone, wherein administrationof the composition to a human being results in the release ofsubstantially all of the morphine from the composition but less than5-10% of the naltrexone from the composition within 24 hours ofadministration, is provided. Also provided are methods for preparingpharmaceutical compositions by, for example, adhering an antagonist to apharmaceutically inert support material, coating the antagonist with aseal coat that includes a sequestering polymer, coating the seal coatwith an agonist, and coating the agonist with a release-retarding orsequestering material. In another embodiment, a method for measuring theamount of antagonist or derivative thereof in a biological sample, theantagonist or derivative having been released from a pharmaceuticalcomposition in vivo, the method comprising the USP paddle method at 37°C., 100 rpm, but further comprising incubation in a buffer containing asurfactant such as Triton X-100, for example.

A particularly preferred embodiment comprises a multiple layerpharmaceutical is described in the Examples is multi-layernaltrexone/morphine dosing unit in an abuse-resistant dosage form.Naltrexone is contained in a sequestering subunit comprising a seal coatcomprising Eudragit® RS and the optimization agents SLS, talc andchloride ions that together prevent release of naltrexone uponhydration. Overlayed onto the sequestering subunit is a layer comprisingmorphine that is released upon hydration in pH 7.5 buffer; thenaltrexone, however, remains within the sequestering subunit under theseconditions. If the unit is modified by, for example, crushing the unit,the sequestering subunit is crushed as well causing the release of bothmorphine and naltrexone therefrom.

Thus, the compositions are particularly well-suited for use inpreventing abuse of a therapeutic agent. In this regard, the inventionalso provides a method of preventing abuse of a therapeutic agent by ahuman being. The method comprises incorporating the therapeutic agentinto any of the compositions of the invention. Upon administration ofthe composition of the invention to the person, the antagonist issubstantially prevented from being released in the gastrointestinaltract for a time period that is greater than 24 hours. However, if aperson tampers with the compositions, the sequestering subunit, which ismechanically fragile, will break and thereby allow the antagonist to bereleased. Since the mechanical fragility of the sequestering subunit isthe same as the therapeutic agent in releasable form, the antagonistwill be mixed with the therapeutic agent, such that separation betweenthe two components is virtually impossible.

A better understanding of the present invention and of its manyadvantages will be had from the following examples, given by way ofillustration.

EXAMPLES

The preparations and experiments described below were actuallyperformed. In certain cases, however, the present tense is utilized.

Example 1 Formulation Evaluation A. Exclusion of Charge-NeutralizationAdditive (SLS)

RB 380-56 Gram per batch Percent Seal-coated sugar spheres Sugar spheres577.9 51.8 Ethylcellulose N50 46.2 4.1 Talc 123.3 11.1 Dibutyl Sebacate4.6 0.4 Naltrexone cores Seal-coated sugar spheres (752.0) (67.4)Naltrexone HCl 27.2 2.4 Klucel LF 5.2 0.5 Talc 12.8 1.1 Ascorbic acid2.8 0.3 Naltrexone pellets Naltrexone cores (800.0) (71.7) Eudragit RS150.0 13.5 Sodium lauryl sulfate 0.0 0.0 Talc 150.0 13.5 DibutylSebacate 15.0 1.3 Total 1115.0 100.0

Method of Preparation:

-   1. Ethylcellulose and dibutyl sebacate were dissolved into ethanol    and talc dispersed into the solution.-   2. The dispersion from 1 was sprayed onto sugar spheres in a Wurster    to form seal-coated sugar spheres.-   3. Klucel LF and ascorbic acid were dissolved into a 20:80 mixture    of water and ethanol. Disperse naltrexone HCl and talc into the    solution.-   4. The naltrexone dispersion from 3 was sprayed onto seal-coated    sugar spheres from 2 in a Wurster to form naltrexone cores.-   5. Eudragit RS and dibutyl debacate were dissolved into ethanol and    talc dispersed into the solution.-   6. The dispersion from 5 was sprayed onto the naltrexone cores from    4 in a Wurster to form naltrexone pellets.-   7. Pellets were dried at 50° C. for 48 hours.-   8. The resulting pellets had a Eudragit RS coat thickness of 47 μm.

Drug Release Results

Dissolution conditions: USP paddle method at 37° C. and 100 rpm, 1 hourin 500 mL of 0.1N HCl followed by 72 hours in 500 mL of 0.05M pH 7.5phosphate buffer.

Conclusions: The results are shown in FIG. 1. The exclusion of SLS fromthe Naltrexone pellet (Eudragit RS) coat results in rapid release ofNaltrexone, with more than 90% release in 24 hours.

B. Variable Amounts of SLS (Eudragit RS Coat Thickness of 53 μm)

Batch Number RB 358-88 RB 358-73 RB 358-83 Gm per Gm per Gm per batchPercent batch Percent batch Percent Seal-coated sugar spheres Sugarspheres 646.1 50.1 646.1 50.0 646.1 49.8 Ethylcellulose 48.5 3.8 48.53.7 48.5 3.7 N50 Talc 126.0 9.8 126.0 9.7 126.0 9.7 Dibutyl 4.9 0.4 4.90.4 4.9 0.4 Sebacate Magnesium 19.4 1.5 19.4 1.5 19.4 1.5 stearateSodium lauryl 1.9 0.2 1.9 0.1 1.9 0.1 sulfate Naltrexone coresSeal-coated (846.7) (65.6) (846.7) (65.5) (846.7) (65.2) sugar spheresNaltrexone HCl 29.5 2.3 29.5 2.3 29.5 2.3 Klucel LF 5.9 0.5 5.9 0.5 5.90.5 Talc 17.8 1.4 17.8 1.4 17.8 1.4 Naltrexone pellets Naltrexone(900.0) (69.7) (900.0) (69.6) (900.0) (69.3) cores Eudragit RS 184.614.3 184.3 14.3 183.7 14.2 Sodium lauryl 3.0 0.23 6.1 0.47 12.3 0.95sulfate Talc 184.6 14.3 184.3 14.3 183.7 14.2 Dibutyl 18.5 1.4 18.4 1.418.4 1.4 Sebacate Total 1290.7 100.0 1293.2 100.0 1298.1 100.0

Method of Preparation:

-   1. Ethylcellulose, sodium lauryl sulfate and dibutyl sebacate were    dissolved into ethanol, and then talc and magnesium stearate were    dispersed into the solution.-   2. The dispersion from 1 was sprayed onto sugar spheres in a Wurster    to form seal-sugar spheres.-   3. Klucel LF was dissolved into a 20:80 mixture of water and    ethanol. Naltrexone HCl and talc were then dispersed into the    solution.-   4. The naltrexone dispersion from 3 was then sprayed onto    seal-coated sugar spheres from 2 in a Wurster to form naltrexone    cores.-   5. Eudragit RS, sodium lauryl sulfate and dibutyl debacate were    dissolved into ethanol, and talc dispersed into the solution.-   6. The dispersion from 5 was sprayed onto naltrexone cores from 4 in    a Wurster to form naltrexone pellets.-   7. The pellets were dried at 50° C. for 13-16.5 hours.-   8. The resulting pellets had a Eudragit RS coat thickness of 51-53    μm.

Drug Release Results

Dissolution conditions: USP paddle method at 37° C. and 100 rpm, 72hours in 500 mL of 0.05M pH 7.5 phosphate buffer

Conclusions: The results are shown in FIG. 2. Addition of a small amountof SLS (1.6% w/w of Eudragit RS) results in charge neutralization ofEudragit RS (theoretically 20% neutralization), and significantly slowsdown the release of naltrexone. Further addition of SLS (3.2% w/w ofEudragit RS) leads to further Eudragit RS charge neutralization(theoretically 41% neutralization), and dramatically slows down releaseof naltrexone. Still higher amount of SLS (6.3% w/w of Eudragit RS),however, results in higher naltrexone release, possibly due toplasticizing effect of SLS.

3. Different Levels of SLS (Eudragit RS Coat Thickness of 65 μm)

Batch Number RB 358-88A RB 358-73A RB 358-83A Gm per Gm per Gm per batchPercent batch Percent batch Percent Seal-coated sugar spheres Sugarspheres 646.1 45.5 646.1 45.4 646.1 45.1 Ethylcellulose 48.5 3.4 48.53.4 48.5 3.4 N50 Talc 126.0 8.9 126.0 8.8 126.0 8.8 Dibutyl 4.9 0.3 4.90.3 4.9 0.3 Sebacate Magnesium 19.4 1.4 19.4 1.4 19.4 1.4 stearateSodium lauryl 1.9 0.1 1.9 0.1 1.9 0.1 sulfate Naltrexone coresSeal-coated (846.7) (59.6) (846.7) (59.4) (846.7) (59.1) sugar spheresNaltrexone HCl 29.5 2.1 29.5 2.1 29.5 2.1 Klucel LF 5.9 0.4 5.9 0.4 5.90.4 Talc 17.8 1.3 17.8 1.2 17.8 1.2 Naltrexone pellets Naltrexone(900.0) (63.4) (900.0) (63.2) (900.0) (62.8) cores Eudragit RS 245.817.3 245.8 17.3 245.8 17.2 Sodium lauryl 4.0 0.3 8.2 0.6 16.4 1.1sulfate Talc 245.8 17.3 245.8 17.3 245.8 17.2 Dibutyl 24.6 1.7 24.6 1.724.6 1.7 Sebacate Total 1420.2 100.0 1424.4 100.0 1432.6 100.0

Method of Preparation

-   1. Ethylcellulose, sodium lauryl sulfate and dibutyl sebacate were    dissolved into ethanol; talc and magnesium stearate were then    dispersed into the solution.-   2. The dispersion from 1 was sprayed onto sugar spheres in a Wurster    to form seal-coated sugar spheres.-   3. Klucel LF was dissolved into a 20:80 mixture of water and    ethanol; naltrexone HCl and talc were then dispersed into the    solution.-   4. The naltrexone dispersion from 3 was then sprayed onto    seal-coated sugar spheres from 2 in a Wurster to form naltrexone    cores.-   5. Eudragit RS, sodium lauryl sulfate and dibutyl debacate were    dissolved into ethanol; talc was then dispersed into the solution.-   6. The dispersion from 5 was sprayed onto naltrexone cores from 4 in    a Wurster to form naltrexone pellets.-   7. The pellets were dried at 50° C. for 1316.5 hours.-   8. The resulting pellets had a Eudragit RS coat thickness of 63-67    μm.

Drug Release Results

Dissolution conditions: USP paddle method at 37° C. and 100 rpm, 72hours in 500 mL of 0.05M pH 7.5 phosphate buffer

Conclusions: The results are shown in FIG. 3. As described above, thereis an optimal ratio of SLS to Eudragit RS.

B. Talc Content Relative to Eudragit RS Polymer

Batch Number RB 358-93 RB 358-73A RB 358-78 Gm Gm Gm per per per batchPercent batch Percent batch Percent Seal-coated sugar spheres Sugarspheres 646.1 46.5 646.1 45.4 646.1 43.9 Ethylcellulose 48.5 3.5 48.53.4 48.5 3.3 N50 Talc 126.0 9.1 126.0 8.8 126.0 8.6 Dibutyl 4.9 0.4 4.90.3 4.9 0.3 Sebacate Magnesium 19.4 1.4 19.4 1.4 19.4 1.3 stearateSodium lauryl 1.9 0.1 1.9 0.1 1.9 0.1 sulfate Naltrexone coresSeal-coated (846.7) (61.0) (846.7) (59.4) (846.7) (57.5) sugar spheresNaltrexone HCl 29.5 2.1 29.5 2.1 29.5 2.0 Klucel LF 5.9 0.4 5.9 0.4 5.90.4 Talc 17.8 1.3 17.8 1.2 17.8 1.2 Naltrexone pellets Naltrexone(900.0) (64.8) (900.0) (63.2) (900.0) (61.1) cores Eudragit RS 266.519.2 245.8 17.3 216.7 14.7 Sodium lauryl 8.8 0.6 8.2 0.6 7.2 0.5 sulfateTalc 186.2 13.4 245.8 17.3 326.3 22.2 Dibutyl 26.6 1.9 24.6 1.7 21.7 1.5Sebacate Total 1388.1 100.0 1424.4 100.0 1471.9 100.0

Method of Preparation

-   1. Dissolve Ethylcellulose, sodium lauryl sulfate and dibutyl    sebacate into ethanol, then disperse talc and magnesium stearate    into the solution.-   2. Spray the dispersion from 1 onto sugar spheres in a Wurster to    form seal-coated sugar spheres.-   3. Dissolve Klucel LF into 20:80 mixture of water and ethanol.    Disperse naltrexone HCl and talc into the solution.-   4. Spray the naltrexone dispersion from 3 onto seal-coated sugar    spheres from 2 in a Wurster to form naltrexone cores.-   5. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl debacate    into ethanol. Disperse talc into the solution.-   6. Spray the dispersion from 5 onto naltrexone cores from 4 in a    Wurster to form naltrexone pellets.-   7. Pellets are dried at 50° C. for 13-16.5 hours.-   8. Resulting pellets have Eudragit RS coat thickness of 63-67 μm.

Drug Release Results

Dissolution conditions: USP paddle method at 37° C. and 100 rpm, 72hours in 500 mL of 0.05M pH 7.5 phosphate buffer

Conclusions: The results of this assay are shown in FIG. 4, anddemonstrate that there is an optimal ratio of talc to Eudragit RS(approximately 1:1). Talc increases the hydrophobicity of the EudragitRS coat, but also reduces film integrity at high amount. FIG. 5demonstrates the transition point in the behavior of the film. FIG. 6demonstrates that there is a distinct optimum in the relationshipbetween film permeability and talc content when using a sugar spherecore.

C. Effects of Osmotic Pressure Reducing Agents on Top of Eudragit RSCoat

Percent Batch Number RB RB 362-28 362-48 RB 362-67 RB 362-65 Naltrexonecores Naltrexone HCl 1.10 0.93 0.89 1.00 Sugar (#20-25 mesh) 24.48 20.5919.80 22.15 HPC (Klucel LF) 0.22 0.19 HPMC, 3 cps 0.18 0.20 Citric acid0.004 0.004 Ascorbic acid 0.004 0.004 BHA 0.004 0.004 Talc 0.66 0.560.54 0.60 Naltrexone pellets Naltrexone cores (26.47) (22.26) (21.41)(23.95) Eudragit RS PO 10.64 8.95 8.62 9.64 SLS 0.36 0.30 0.29 0.33 DBS1.06 0.89 0.85 0.95 Talc 10.89 9.16 8.62 9.64 Naltrexone-morphine coresNaltrexone pellets (49.41) (41.55) (39.78) (44.50) Morphine sulfate26.05 21.70 21.70 24.76 Confectioner's sugar 13.66 9.32 Sodium chloride6.43 7.01 HPMC, 3 cps 2.32 3.46 3.13 4.10 Naltrexone-morphine pelletsNaltrexone-morphine (77.78) (80.37) (80.37) (80.37) cores EthylcelluloseN50 7.48 7.07 7.07 7.07 PEG 6000 3.59 2.88 2.81 2.62 Eudragit L100-552.10 1.70 1.77 1.96 DEP 1.65 1.44 1.44 1.44 Talc 7.41 6.54 6.54 6.54Total 100.00 100.00 100.00 100.00

Method of Preparation:

-   1. Klucel LF or HPMC (with or without citric acid, ascorbic acid and    butylated hydroxyanisole) was dissolved into 20:80 mixture of water    and ethanol; naltrexone HCl and talc were dispersed into the    solution.-   2. The naltrexone dispersion from 1 was sprayed onto sugar spheres    in a Wurster to form naltrexone cores.-   3. Eudragit RS, sodium lauryl sulfate and dibutyl debacate were    dissolved into ethanol; talc was then dispersed into the solution.-   4. The dispersion from 3 was sprayed onto naltrexone cores from 2 in    a Wurster to form naltrexone pellets.-   5. The Naltrexone pellets were dried at 50° C. for either 12 hours    (RB 362-28 and RB 362-48) or 65 hours (RB 362-67 and RB 362-65).-   6. The resulting pellets had a Eudragit RS coat thickness of 85-90    μm.-   7. Sodium chloride and hypromellose were then dissolved into water.-   8. HPMC was dissolved into either water or mixture of ethanol and    water.-   9. Sodium chloride was dissolved into the HPMC solution from 8.-   10. Confectioner's sugar was dispersed into the HPMC solution from    8.-   11. Morphine sulfate was dispersed into the HPMC solution from 8.-   12.    -   a. For RB 362-28, spray onto naltrexone pellets in 5 in a rotor        the solution from 8, followed by the dispersion from 11, to form        naltrexone-morphine cores.    -   b. For RB 362-48, spray onto naltrexone pellets in 5 in a rotor        the solution from 8, followed by the dispersion from 10,        followed by the solution from 8, and followed by the dispersion        from 11, to form naltrexone-morphine cores.    -   c. For RB 362-67, spray onto naltrexone pellets in 5 in a rotor        the solution from 9, followed by the dispersion from 10,        followed by the solution from 8, and followed by the dispersion        from 11, to form naltrexone-morphine cores.    -   d. For RB 362-65, spray onto naltrexone pellets in 5 in a rotor        the solution from 9; followed by the solution from 8, and        followed by the dispersion from 11, to form naltrexone-morphine        cores.-   13. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethyl phthalate    were dissolved into ethanol and talc was dispersed into the    solution.-   14. The dispersion from 13 was sprayed onto naltrexone-morphine    cores in 12 to form naltrexone-morphine pellets.

Drug Release Results:

Dissolution conditions: USP paddle method at 37° C. and 100 rpm, 72hours in 500 mL of 0.05M pH 7.5 phosphate buffer; or, USP paddle methodat 37° C. and 100 rpm, 1 hour in 0.1N HCl, followed by 72 hours in 0.05MpH 7.5 phosphate buffer

Results:

% NT release at the end of Batch Number dissolution RB 362-28 Naltrexonepellet 2 Naltrexone-morphine pellet 7.9 RB 362-48 Naltrexone pellet 2Naltrexone-morphine pellet 68.5 RB 362-67 Naltrexone pellet 0Naltrexone-morphine pellet 25 RB 362-65 Naltrexone pellet 0.2Naltrexone-morphine pellet 1.4

Conclusions: Sugar has a detrimental effect on NT release. The use ofNaCl/HPMC provides the desired NT release profile.

II. Proof of Concept Study, 16 mg Naltrexone HCl (20-727-1N)

PI-1460 PI-1461 mg/unit Percent mg/unit Percent Naltrexone HCl 8 2.23 82.07 Sugar sphere (#20-25 mesh) 177.9 49.6 Cellets (#20-25 mesh) 228.359.1 HPC (Klucel LF) 1.6 0.4 1.6 0.4 Talc 4.8 1.3 4.8 1.2 Eudragit RS PO77.3 21.5 66.2 17.2 SLS 2.6 0.7 2.3 0.6 DBS 7.7 2.1 6.6 1.7 Talc 79.122.0 68.2 17.7 Total 359 100.0 386 100.0

A. Method of Preparation

-   -   1. Dissolve Klucel LF into 20:80 mixture of water and ethanol.        Disperse naltrexone HCl and talc into the solution.    -   2. Spray the naltrexone dispersion from 1 onto sugar spheres        (for PI-1460) or Cellets (for PI-1461) in a Wurster to form        naltrexone cores.    -   3. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl        sebacate into ethanol. Disperse talc into the solution.    -   4. Spray the dispersion from 3 onto naltrexone cores from 2 in a        Wurster to form naltrexone pellets.    -   5. The naltrexone pellets are dried in an oven at 50° C. for 12        hours.    -   6. Resulting pellets have Eudragit RS coat thickness of 90 μm        (for PI-1460) and 60 μm (for PI-1461).    -   7. The pellets are filled into capsules.

B. In-Vitro Drug Release—

-   -   Method—USP paddle method at 37° C. and 100 rpm; 1 hour in 0.1N        HCl, then 72 hours in 0.05M pH 7.5 phosphate buffer    -   Results—Percent of NT released at 73 hours for PI-1460=2%        -   Percent of NT released at 73 hours for PI-1461=0%

C. In-Vivo Biostudy—

Single-dose, open-label, two-period pilot study in 26 healthy subjectsunder fasting conditions:

-   -   Period 1: Oral liquid containing 16 mg naltrexone (N=26)    -   Period 2: 2 capsules of PI-1460 (N=13) or PI-1461 (N=13)

Blood samples were withdrawn from prior to dosing and from 0.5 to 72hours after dosing, and analyzed for plasma naltrexone and6-beta-Naltrexol levels. Limit of quantitation was 20.0 pg/mL fornaltrexone and 0.250 pg/mL for 6-beta-Naltrexol. The data is shown inFIGS. 7-10.

Summary of Pharmacokinetic Results—

6-beta-Naltrexol Naltrexone NTX 2 capsules 2 capsules NTX 2 capsules 2capsules Solution of PI-1460 of PI-1461 Solution of PI-1460 of PI-1461Tmax (hr) 0.75 43.02 32.01 0.75 24.38 (N = 4) 23.21 (N = 10) Cmax(pg/mL) 24600 298 834 2950  22.4 (N = 11) 60.7 AUC_(last) (pg * h/mL)205800 10460 32530 8925 200.2 (N = 11) 1258 AUC_(linf) (pg * h/mL)212700 9569 (N = 23) Relative Bioavailability to an oral solution: CmaxRatio 1.21% 3.39% 0.76% 2.06% (Capsule/Solution) AUC_(last) Ratio 5.08%15.80% 2.24% 14.08% (Capsule/Solution) N = 26 for Solution, unlessspecified otherwise N = 12 for PI-1460 or PI-1461, unless specifiedotherwise

D. Conclusion—

-   -   1. Plasma 6-beta-naltrexol levels provide a more accurate        indicator of bioavailability than plasma NT levels, due to its        higher plasma levels and higher analytical sensitivity.    -   2. Using 6-beta-naltrexol AUC_(last) ratio of capsules to        solution as indicator of cumulative in vivo NT release,        significant sequestering of naltrexone is observed to 72 hours        under fasting condition. Using Cellets as seed cores resulted in        three times higher observed in vivo NT release than sugar.        However, NT pellets using Cellet have lower RS coat thickness        than Sugar (60 μm versus 90 μm), because at 60 μm, Cellet NT        pellets have slightly better in vitro dissolution performance        than Sugar NT pellets at 90 μm.        III. Optimization Study #1, Morphine Sulfate and Naltrexone 60        mg/2.4 mg (ALPH-KNT-002)

PI-1462 PI-1463 mg/unit Percent mg/unit Percent Naltrexone coresNaltrexone HCl 2.4 0.96 2.4 0.94 Cellets (#20-25 mesh) 67.1 26.8 59.823.4 HPC (Klucel LF) 0.5 0.2 0.5 0.2 Citric acid 0.01 0.0040 0.01 0.004Ascorbic acid 0.01 0.0040 0.01 0.004 BHA 0.01 0.0040 0.01 0.004 Talc1.38 0.6 1.57 0.6 Subtotal 71.4 28.5 64.3 25.1 Naltrexone pelletsNaltrexone cores (71.4) (28.5) (64.3) (25.1) Eudragit RS PO 19.5 7.8 2610.2 SLS 0.7 0.3 0.9 0.4 DBS 2 0.8 2.6 1.0 Talc 20 8.0 26.6 10.4Subtotal 113.6 45.4 120.4 47.1 Naltrexone-morphine cores Naltrexonepellets (113.6) (45.4) (120.4) (47.1) Morphine sulfate 58.7 23.5 56.322.0 Sodium chloride 16.6 6.6 16.6 6.5 HPMC, 3 cps 13.6 5.4 13.5 5.3Subtotal 202.5 80.9 206.8 80.8 Naltrexone-morphine pelletsNaltrexone-morphine cores (202.5) (80.9) (206.8) (80.8) EthylcelluloseN50 16 6.4 16.4 6.4 PEG 6000 7.4 3.0 7.6 3.0 Eudragit L100-55 3.5 1.43.6 1.4 DEP 3.3 1.3 3.4 1.3 Talc 17.5 7.0 18 7.0 Total 250.2 100.0 255.8100.0

A. Method of Preparation—

-   -   1. Dissolve Klucel LF, citric acid, ascorbic acid and butylated        hydroxyanisole into 20:80 mixture of water and ethanol. Disperse        naltrexone HCl and talc into the solution.    -   2. Spray the naltrexone dispersion from 1 onto Cellets in a        Wurster to form naltrexone cores.    -   3. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl        debacate into ethanol. Disperse talc into the solution.    -   4. Spray the dispersion from 3 onto naltrexone cores from 2 in a        Wurster to form naltrexone pellets.    -   5. The Naltrexone pellets are dried at 50° C. for 48 hours.    -   6. Resulting pellets have a Eudragit RS coat thickness of 60 μm        for PI-1462 and 90 μm for PI-1463.    -   7. Dissolve sodium chloride and hypromellose into water.    -   8. Dissolve hypromellose into 10:90 mixture of water and        ethanol. Disperse morphine sulfate into the solution.    -   9. Spray the solution from 7 followed by the dispersion from 8        onto naltrexone pellets in 5 in a rotor to form        naltrexone-morphine cores.    -   10. Dissolve ethylcellulose, PEG 6000, Eudragit L100-55 and        diethyl phthalate into ethanol. Disperse talc into the solution.    -   11. Spray the dispersion from 10 onto naltrexone-morphine cores        in 9 to form naltrexone-morphine pellets.    -   12. The pellets are filled into capsules.

B. In-Vitro Drug Release—

-   -   Method—USP paddle method at 37° C. and 100 rpm        -   1 hour in 0.1N HCl, then 72 hours in 0.05M pH 7.5 phosphate            buffer    -   Results—Percent of NT released at 73 hours for PI-1462=0%        -   Percent of NT released at 73 hours for PI-1463=0%

C. In-Vivo Study

This is a single-dose, open-label, single-period study in which twogroups of eight subjects received one dose of either PI-1462 or PI-1463under fasting condition. Blood samples were drawn prior to doseadministration and at 0.5 to 168 hours post-dose. Limits of quantitationare 4.00 pg/mL for naltrexone and 0.250 pg/mL for 6-beta-naltrexol. Thedata is shown in FIGS. 11-12.

2. Summary of Pharmacokinetics Parameters

6-beta-Naltrexol Naltrexone PI-1462 PI-1463 PI-1462 PI-1463 Tmax (hr)49.52 40.53 42.03 37.75 (N = 3) Cmax (pg/mL) 349 285 25.3 35.5AUC_(last) (pg * h/mL) 16850 11130 705.1 835.0  AUC∞ (pg * h/mL) 1704011170  1057 (N = 4)  1711 (N = 3) T½ (hr) 18.18 14.49 14.15 (N = 4) 8.89 (N = 3) Relative Bioavailability to an oral solution(Dose-adjusted) Cmax Ratio (Test/Solution) 9.46% 7.72% 5.71%  8.02%AUC_(last) Ratio (Test/Solution) 54.58% 36.05% 52.67% 62.37% AUC∞ Ratio(Test/Solution) 53.41% 35.01% 78.95% 119.2% N = 8, unless specifiedotherwise

3. Conclusion

-   a. Plasma 6-beta-naltrexol levels provide more consistent indication    of bioavailability than Naltrexone.-   b. There is significant release in-vivo in both formulations, as    indicated by relative bioavailability based on AUC∞ ratios. 90 μm    coat thickness results in less release than 60 μm. Comparing PI-1463    (Opt #1) with PI-1461 (POC), the coating of morphine/NaCl/Kadian ER    coat on top of Naltrexone pellet causes more than three-fold    increase in NT release.-   c. 7-day duration of study allows 6-beta-naltrexol to return to    baseline.-   d. There is clearly no in vitro/in vivo correlation regarding NT    release, using conventional buffer system. In vitro dissolution    shows 0% NT release at the end of 72 hours, but in vivo data reveals    significant NT release.    IV. Optimization Studies #2 and #3, Morphine Sulfate and Naltrexone    HCl 60 mg/2.4 mg (20-778-1N and 20-779-1N)

PI-1465 PI-1466 mg/unit Percent mg/unit Percent Sealed-coated sugarspheres Sugar spheres (#20-25 mesh) 52.1 16.0 53.1 14.6 EthylcelluloseN50 3.9 1.2 3.98 1.1 Mag Stearate 1.6 0.5 1.6 0.4 Dibutyl Sebecate 0.40.1 0.4 0.1 Talc 10 3.1 10.27 2.8 Subtotal 68.0 20.9 69.4 19.0Naltrexone cores Sealed sugar spheres (68.0) (20.9) (69.4) (19.0)Naltrexone HCl 2.4 0.74 2.4 0.66 HPC (Klucel LF) 0.5 0.2 0.5 0.1 Citricacid 0.01 0.0031 0.01 0.0027 Ascorbic acid 0.01 0.0031 0.01 0.0027Butylated Hydroxyanisole 0.01 0.0031 0.01 0.0027 Talc 1.4 0.4 1.43 0.4Subtotal 72.3 22.3 73.7 20.2 Naltrexone pellets Naltrexone cores (144.7)(44.5) (147.4) (40.4) Eudragit RS PO 25.4 7.8 38.7 10.6 Sodium laurylsulfate 0.9 0.3 1.31 0.4 Dibutyl Sebecate 2.53 0.8 3.87 1.1 Talc 26 8.038.7 10.6 Subtotal 199.5 61.4 230.0 63.1 Naltrexone-morphine coresNaltrexone pellets (199.5) (61.4) (230.0) (63.1) Morphine sulfate 59.318.2 59.5 16.3 Sodium chloride 17.5 5.4 20.1 5.5 Hypromellose 2910, 3cps 14.2 4.4 15.1 4.1 Subtotal 290.5 89.4 324.7 89.0 Naltrexone-morphinepellets Naltrexone-morphine cores (290.5) (89.4) (324.7) (89.0)Ethylcellulose N50 11.51 3.5 13.1 3.6 Polyethylene glycol 6000 5.3 1.66.1 1.7 Eudragit L100-55 2.1 0.6 2.85 0.8 Diethyl Phthalate 2.4 0.7 2.80.8 Talc 13.23 4.1 15.2 4.2 Total 325.0 100.0 364.8 100.0

A. Method of Preparation—

-   -   1. Dissolve Ethylcellulose and dibutyl sebacate into ethanol,        then disperse talc and magnesium stearate into the solution.    -   2. Spray the dispersion from 1 onto sugar spheres in a Wurster        to form seal-coated sugar spheres (25 μm seal coat thickness).    -   3. Dissolve Klucel LF, citric acid, ascorbic acid and butylated        hydroxyanisole into 20:80 mixture of water and ethanol. Disperse        naltrexone HCl and talc into the solution.    -   4. Spray the naltrexone dispersion from 3 onto seal-coated sugar        spheres from 2 in a Wurster to form naltrexone cores.    -   5. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl        debacate into ethanol. Disperse talc into the solution.    -   6. Spray the dispersion from 5 onto naltrexone cores from 4 in a        Wurster to form naltrexone pellets.    -   7. The Naltrexone pellets are dried at 50° C. for 48 hours.    -   8. Resulting pellets have a Eudragit RS coat thickness of 90 μm        for PI-1465 and 120 μm for PI-1466.    -   9. Dissolve sodium chloride and hypromellose into water.    -   10. Dissolve hypromellose into 10:90 mixture of water and        ethanol. Disperse morphine sulfate into the solution.    -   11. Spray the solution from 9 followed by the dispersion from 10        onto naltrexone pellets in 7 in a rotor to form        naltrexone-morphine cores.    -   12. Dissolve ethylcellulose, PEG 6000, Eudragit L100-55 and        diethyl phthalate into ethanol. Disperse talc into the solution.    -   13. Spray the dispersion from 12 onto naltrexone-morphine cores        in 11 to form naltrexone-morphine pellets.    -   14. The pellets are filled into capsules.

B. In-Vitro Drug Release—

-   -   1. Method—USP paddle method at 37° C. and 100 rpm        -   1 hour in 0.1N HCl, then 72 hours in 0.05 M pH 7.5 phosphate            buffer    -   Results—Percent of NT released at 73 hours for PI-1465=1%        -   Percent of NT released at 73 hours for PI-1466=0%    -   2. Method—USP paddle method at 37° C. and 100 rpm        -   72 hrs in 0.2% Triton X-100/0.2% sodium acetate/0.002N HCl,            pH 5.5        -   The data is shown in FIG. 13.

C. In-Vivo Study #1

This is a single-dose, open-label, single-period study in which twogroups of eight subjects received one dose of either PI-1465 or PI-1466under fasting condition. Blood samples were drawn prior to doseadministration and at 0.5 to 168 hours post-dose. Limits of quantitationare 4.00 pg/mL for naltrexone and 0.250 pg/mL for 6-beta-naltrexol. Thedata is shown in FIGS. 14-15.

2. Summary of Pharmacokinetics Parameters

6-beta-Naltrexol Naltrexone PI-1465 PI-1466 PI-1465 PI-1466 Tmax (hr)58.51 79.50 50.30 (N = 7) 45.17 (N = 3) Cmax (pg/mL) 1060 72.6 139.346.2 AUC_(last) (pg * h/mL) 54693 23473 3713 744 AUC∞ (pg * h/mL) 5626023940  7213 (N = 4)  5943 (N = 2) T½ (hr) 20.90 15.09 16.47 (N = 4)34.10 (N = 2) Relative Bioavailability to an oral solution(Dose-adjusted) Cmax Ratio (Test/Solution) 4.31% 1.97% 4.72% 1.57%AUC_(last) Ratio (Test/Solution) 26.58% 11.41% 41.60% 8.34% AUC∞ Ratio(Test/Solution) 26.45% 11.26% 75.38% 62.11% N = 8, unless specifiedotherwise

3. Conclusions

-   -   a. Presence of surfactant in the dissolution medium (second        in-vitro drug release method) provides better        in-vitro-in-vivo-correlation than buffer alone (first in-vitro        drug release method).    -   b. Kadian NT pellets (additional layering of        NaCl/morphine/Kadian ER coat on top of naltrexone pellets) had a        higher release of naltrexone in vivo than Naltrexone pellets        alone. PI-1465 containing the seal coat and the same naltrexone        pellet coat thickness as PI-1460 from POC without seal coat (90        μm), had more than 5 times more release of naltrexone. Even an        increase in Naltrexone pellet coat thickness to 120 μm (PI-1466)        still gave twice the release of naltrexone.

D. In-Vivo Study #2

This is a single-dose, open-label, single-period study in which fourgroups of four healthy subjects received a single dose of either PI-1465or PI-1466 under either fasting or fed conditions. Blood samples weredrawn prior to dose administration and at 0.5 to 168 hours post-dose.Limits of quantitation are 4.00 pg/mL for naltrexone and 0.250 pg/mL for6-beta-naltrexol. The data is shown in FIGS. 16-17.

1. Summary of Pharmacokinetic Parameters

a. Naltrexone

PI-1465 PI-1466 Fast Fed Fast Fed Tmax (hr) 72.00 26.67 (N = 3) 60.00 (N= 2) 32.00 (N = 3) Cmax (pg/mL) 107.3 279.3 35.73 262 AUC_(last) (pg *h/mL) 2825 4135 1319 4611 AUC∞ (pg * h/mL)  3593 (N = 1)  6787 (N = 2) 3651 (N = 2) — T½ (hr) 15.26 (N = 1) 20.98 (N = 2) 24.75 (N = 2) —Relative Bioavailability to an oral solution(Dose-adjusted) Cmax Ratio(Test/Solution) 3.64% 9.47% 1.21% 8.89% AUC_(last) Ratio (Test/Solution)31.65% 46.33% 14.78% 51.66% AUC∞ Ratio (Test/Solution) 37.55% 70.93%38.15% — N = 4, unless specified otherwise

b. 6-beta-Naltrexol Levels

PI-1465 PI-1466 Fast Fed Fast Fed Tmax (hr) 69.00 29.00 69.00 36.00 Cmax(pg/mL) 1280 3787 873 2680 AUC_(last) (pg * h/mL) 53307 120400 4714078533 AUC∞ (pg * h/mL) 53547 122533 47920 78867 T½ (hr) 19.21 18.1720.69 20.19 Relative Bioavailability to an oral solution Cmax Ratio(Test/Solution) 5.20% 15.39% 3.55% 10.89% AUC_(last) Ratio(Test/Solution) 25.90% 58.50% 22.91% 38.16% AUC∞ Ratio (Test/Solution)25.17% 57.61% 22.53% 37.08% N = 4, unless specified otherwise

2. Conclusion

-   -   a. There is significant food effect, where the lag time was        reduced and NT release was increased in the presence of food.        There is a two-fold increase in NT release for PI-1465 and        1.5-fold increase for PI-1466 in the presence of food.    -   b. There is some subject group variability. Comparing PI-1466 in        both in-vivo study #1 and #2, although the same product was        used, for fasting condition, there was a two-fold difference in        AUC. For PI-1465, the AUC was similar between the two studies.        V. Optimization Study #4, Morphine Sulfate and Naltrexone HCl 60        mg/4.8 mg (20-780-1N)

PI-1495 PI-1496 mg/unit Percent mg/unit Percent Sealed-coated sugarspheres Sugar spheres (#25-30 mesh) 37.2 11.7 37.1 11.9 EthylcelluloseN50 6.2 1.9 6.2 2.0 Mag Stearate 2.5 0.8 2.5 0.8 DBS 0.6 0.2 0.6 0.2Talc 15.5 4.9 15.5 5.0 Subtotal 62.0 19.4 61.9 19.9 Naltrexone coresSealed sugar spheres (62.0) (19.4) (61.9) (19.9) Naltrexone HCl 4.8 1.504.8 1.54 HPC (Klucel LF) 0.9 0.3 0.9 0.3 Ascorbic acid 0.5 0.2 0.5 0.2Talc 2.27 0.7 2.24 0.7 Subtotal 70.5 22.1 70.3 22.6 Naltrexone pelletsNaltrexone cores (70.5) (22.1) (70.3) (22.6) Eudragit RS PO 53.3 16.753.3 17.1 SLS 1.8 0.6 1.8 0.6 DBS 5.36 1.7 5.36 1.7 Talc 52.1 16.3 52.116.8 Subtotal 183.0 57.4 182.9 58.8 Naltrexone-morphine cores Naltrexonepellets (183.0) (57.4) (182.9) (58.8) Morphine sulfate 59.9 18.8 59.719.2 Sodium chloride 11.2 3.5 HPC (Klucel LF) 7.3 2.3 4.76 1.5 HPMC, 3cps 7.6 2.4 Subtotal 261.4 82.0 255.0 82.0 Naltrexone-morphine pelletsNaltrexone-morphine cores (261.4) (82.0) (255.0) (82.0) EthylcelluloseN50 19.81 6.2 19.31 6.2 PEG 6000 9.16 2.9 8.9 2.9 Eudragit L100-55 4.31.3 4.2 1.4 DEP 4.12 1.3 4 1.3 Talc 20.13 6.3 19.62 6.3 Total 319.0100.0 311.0 100.0

A. Method of Preparation—

-   -   1. Dissolve Ethylcellulose and dibutyl sebacate into ethanol,        then disperse talc and magnesium stearate into the solution.    -   2. Spray the dispersion from 1 onto sugar spheres in a Wurster        to form seal-coated sugar spheres (50 μm seal coat).    -   3. Dissolve Klucel LF and ascorbic acid into 20:80 mixture of        water and ethanol. Disperse naltrexone HCl and talc into the        solution.    -   4. Spray the naltrexone dispersion from 3 onto seal-coated sugar        spheres from 2 in a Wurster to form naltrexone cores.    -   5. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl        debacate into ethanol. Disperse talc into the solution.    -   6. Spray the dispersion from 5 onto naltrexone cores from 4 in a        Wurster to form naltrexone pellets.    -   7. The Naltrexone pellets are dried at 50° C. for 48 hours.    -   8. Resulting pellets have a Eudragit RS coat thickness of 150 μm        for both PI-1495 PI-1496.    -   9. (Only for PI-1495) Dissolve sodium chloride and hypromellose        into water.    -   10. Dissolve hypromellose into 10:90 mixture of water and        ethanol. Disperse morphine sulfate into the solution.    -   11. (Only for PI-1495) Spray the solution from 9 followed by the        dispersion from 10 onto naltrexone pellets in 7 in a rotor to        form naltrexone-morphine cores.    -   12. (Only for PI-1496) Spray the dispersion from 10 onto        naltrexone pellets in 7 in a rotor to form naltrexone-morphine        cores.    -   13. Dissolve ethylcellulose, PEG 6000, Eudragit L100-55 and        diethyl phthalate into ethanol. Disperse talc into the solution.    -   14. Spray the dispersion from 12 onto naltrexone-morphine cores        in 11 or 12 to form naltrexone-morphine pellets.    -   15. The pellets are filled into capsules.

B. In-Vitro Drug Release—

-   -   1. Method—USP paddle method at 37° C. and 100 rpm        -   1 hour in 0.1N HCl, then 72 hours in 0.05M pH 7.5 phosphate            buffer    -   Results—Percent of NT released at 73 hours for PI-1495=0%        -   Percent of NT released at 73 hours for PI-1496=0%    -   2. Method—USP paddle method at 37° C. and 100 rpm        -   72 hrs in 0.2% Triton X-100/0.2% sodium acetate/0.002N HCl,            pH 5.5    -   Results—Percent of NT released at 73 hours for PI-1495=0%        -   Percent of NT released at 73 hours for PI-1496=0%

C. In-Vivo Study

This is a single-dose, open-label, two period study in which two groupsof eight subjects received one dose of either PI-1495 or PI-1496. Eachsubject received an assigned treatment sequence based on a randomizationschedule under fasting and non-fasting conditions. Blood samples weredrawn prior to dose administration and at 0.5 to 168 hours post-dose.Limits of quantitation are 4.00 pg/mL for naltrexone and 0.250 pg/mL for6-beta-naltrexol. The data is shown in FIGS. 18-19.

2. Summary of Pharmacokinetic Parameters

a. Naltrexone

PI-1495 PI-1496 Fast Fed Fast Fed Tmax (hr) 54.00 (N = 2) 14.34 (N = 3) 55.20 (N = 5) 41.60 (N = 5) Cmax (pg/mL) 8.53 6.32 (N = 7) 24.23 (N = 7)45.67 (N = 7) AUC_(last) (pg * h/mL) 100.8 75.9 (N = 7) 500.6 (N = 7) 1265 (N = 7) AUC∞ (pg * h/mL) — — 2105.3 (N = 2)   3737 (N = 2) T½ (hr)— — 44.56 (N = 2) 33.17 (N = 2) Relative Bioavailability to an oralsolution (Dose-adjusted) Cmax Ratio (Test/Solution) 0.29% 0.21% 0.82%1.55% AUC_(last) Ratio (Test/Solution) 1.13% 0.85% 5.61% 14.17%  AUC∞Ratio (Test/Solution) — — 22.0% 39.1% N = 8, unless specified otherwise

b. 6-beta-Naltrexol Levels

PI-1495 PI-1496 Fast Fed Fast Fed Tmax (hr) 69.00 41.44 (N = 7) 70.5167.63 Cmax (pg/mL) 116.3 151.7 (N = 7) 303.3 656.7 AUC_(last) (pg *h/mL) 5043  7332 (N − 7) 14653 27503 AUC∞ (pg * h/mL) 5607  8449 (N = 6)14930 27827 T½ (hr) 20.97 16.69 (N = 7) 16.29 22.59 RelativeBioavailability to an oral solution (Dose-adjusted) Cmax Ratio(Test/Solution) 0.47% 0.62% 1.23% 2.67% AUC_(last) Ratio (Test/Solution)2.45% 3.45% 7.12% 13.36% AUC∞ Ratio (Test/Solution) 2.64% 3.97% 7.02%13.08% N = 8, unless specified otherwise

3. Conclusion

-   -   a. Kadian NT pellets with naltrexone pellet coat thickness of        150 μm had comparable naltrexone release as NT pellets with 90        μm coat thickness. This comparable NT release may also be        attributed from the presence of 50 μm seal coat on the sugar        spheres used in Kadian NT pellets.    -   b. Significant NT sequestering was observed, both at fasting        (>97%) and fed states (>96%).    -   c. Kadian NT pellets containing sodium chloride immediately        above the naltrexone pellet coat (PI-1495) had half the release        of naltrexone compared to Kadian NT pellet without sodium        chloride (PI-1496), consistent with in vitro results.    -   d. There is again food effect observed. Lag time was        significantly reduced.        VI. Optimization Study #5, Morphine Sulfate and Naltrexone HCl        60 mg/2.4 mg (20-903-AU)

PI-1510 mg/unit Percent Sealed sugar spheres Sugar spheres (#25-30 mesh)39.9 12.2 Ethylcellulose N50 6.5 2.0 Mag Stearate 2.6 0.8 DBS 0.7 0.2Talc 16.7 5.1 Subtotal 66.4 20.3 Naltrexone cores Sealed sugar spheres(66.4) (20.3) Naltrexone HCl 2.4 0.73 HPC (Klucel LF) 0.5 0.1 Ascorbicacid 0.2 0.1 Talc 1.1 0.4 Subtotal 70.6 21.6 Naltrexone pelletsNaltrexone cores (70.6) (21.6) Eudragit RS PO 53.0 16.2 SLS 1.8 0.6 DBS5.3 1.6 Talc 53.0 16.2 Subtotal 183.7 56.2 Naltrexone-morphine coresNaltrexone pellets (183.7) (56.2) Morphine sulfate 60.1 18.4 Sodiumchloride 12.5 3.8 HPC (Klucel LF) 6.2 1.9 Subtotal 262.4 80.2Naltrexone-morphine pellets Naltrexone-morphine cores (262.4) (80.2)Ethylcellulose N50 22.9 7.0 PEG 6000 10.6 3.2 Eudragit L100-55 5.0 1.5DEP 4.7 1.5 Talc 21.5 6.6 Total 327.1 100.0

B. Method of Preparation—

-   -   1. Dissolve Ethylcellulose and dibutyl sebacate into ethanol,        then disperse talc and magnesium stearate into the solution.    -   2. Spray the dispersion from 1 onto sugar spheres in a Wurster        to form seal-coated sugar spheres (50 μm seal coat).    -   3. Dissolve Klucel LF and ascorbic acid into 20:80 mixture of        water and ethanol. Disperse naltrexone HCl and talc into the        solution.    -   4. Spray the naltrexone dispersion from 3 onto seal-coated sugar        spheres from 2 in a Wurster to form naltrexone cores.    -   5. Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl        sebacate into ethanol. Disperse talc into the solution.    -   6. Spray the dispersion from 5 onto naltrexone cores from 4 in a        Wurster to form naltrexone pellets.    -   7. The Naltrexone pellets are dried at 50° C. for 48 hours.    -   8. Resulting pellets have a Eudragit RS coat thickness of 150        μm.    -   9. Dissolve sodium chloride and hypromellose into water.    -   10. Dissolve hypromellose into 10:90 mixture of water and        ethanol. Disperse morphine sulfate into the solution.    -   11. Spray the solution from 9 followed by the dispersion from 10        onto naltrexone pellets in 7 in a rotor to form        naltrexone-morphine cores.    -   12. Dissolve ethylcellulose, PEG 6000, Eudragit L100-55 and        diethyl phthalate into ethanol. Disperse talc into the solution.    -   13. Spray the dispersion from 12 onto naltrexone-morphine cores        in 11 or 12 to form naltrexone-morphine pellets.    -   14. The pellets are filled into capsules.

B. In-Vitro Drug Release—

-   -   1. Method—USP paddle method at 37° C. and 100 rpm        -   1 hour in 0.1N HCl, then 72 hours in 0.05M pH 7.5 phosphate            buffer    -   Results—Percent of NT released at 73 hours for =0%    -   2. Method—USP paddle method at 37° C. and 100 rpm        -   72 hrs in 0.2% Triton X-100/0.2% sodium acetate/0.002N HCl,            pH 5.5    -   Results—Percent of NT released at 73 hours=0%

C. In-Vivo Study

This is a single-dose, open-label, two period study in which eightsubjects were randomized to receive one dose of PI-1510 under eitherfasted or fed state during Study Period 1 and alternate fasted or fedstate for Study Period 2. Blood samples were drawn prior to doseadministration and at 0.5 to 168 hours post-dose. Limits of quantitationare 4.00 pg/mL for naltrexone and 0.250 pg/mL for 6-beta-naltrexol. Thedata is shown in FIGS. 20 and 21.

2. Summary of Pharmacokinetic Parameters

a. 6-beta-Naltrexol Levels

PI-1510 Fast Fed Tmax (hr) 45.00 (N = 6) 57.29 (N = 7) Cmax (pg/mL) 16.125.0 AUC_(last) (pg * h/mL) 609.2 1057 AUC∞ (pg * h/mL) 1233  1431 (N =6) T½ (hr) 17.36 17.48 (N = 6) Relative Bioavailability to an oralsolution (Dose- adjusted) Cmax Ratio (Test/Solution) 0.44% 0.68%AUC_(last) Ratio (Test/Solution) 1.97% 3.42% AUC∞ Ratio (Test/Solution)3.86% 4.49% N = 8, unless specified otherwise

3. Conclusion

-   -   a. PI-1510 and PI-1495 are comparable. The reduction in        naltrexone loading in the pellets (from 1.5% in PI-1495 to 0.7%        in PI-1510) does not seem to affect NT release.    -   b. Significant NT sequestering was observed, both at fasting        (>96%) and fed states (>95%).    -   c. The food effect observed was modest in terms of total NT        release. However, the lag time was significantly reduced in the        presence of food. There were subjects with multiple peaks of        release.        VII. Summary of NT Release from All In-Vivo Studies        BA (Cmax)=Relative bioavailability based on Cmax=Dose-adjusted        ratio of Cmax (NT/KNT pellet) to Cmax(NT soln)        BA (AUC last)=Relative bioavailability based on AUC        last=Dose-adjusted ratio of AUC last (NT/KNT pellet) to AU        BA (AUC inf)=Relative bioavailability based on AUC        inf=Dose-adjusted ratio of AUC inf (NT/KNT pellet)        Total in-vivo cumulative NT release can be extrapolated from BA        (AUC inf) calculations from 6-beta-Naltrexol plasma levels

BA BA (AUC last) (Cmax) (%) (%) BA (AUC inf) (%) POC PI-1460 Fast Avg ±SD 1.2 ± 0.9 5.1 ± 3.1 Range 0.32-2.99  1.92-10.65 PI-1461 Fast Avg ± SD3.1 ± 2.4 15.8 ± 11.9 Range  0.7-10.3  2.8-49.2 OPTIM. #1 PI-1462 FastAvg ± SD 9.5 ± 2.8 54.6 ± 21.0 53.4 ± 20.6 Range  5.7-13.0 26.3-86.325.6-84.4 PI-1463 Fast Avg ± SD 7.7 ± 3.7 36.1 ± 18.2 35.0 ± 17.7 Range 0.8-12.4  3.9-59.2  3.8-57.3 OPTIM. #2 and #3 PI-1465 Fast 1 Avg ± SD4.3 ± 6.2 26.6 ± 35.4 26.4 ± 35.0 Range  0.1-18.6  0.1-111.6  0.1-110.5Fast 2 Avg ± SD 5.2 ± 3.9 25.9 ± 15.7 25.2 ± 15.2 Range  1.8-10.5 9.6-41.5  9.4-40.2 Fed Avg ± SD 15.4 ± 12.5 58.5 ± 34.6 57.6 ± 34.4Range  1.4-31.2 11.9-90.6 11.5-90.6 PI-1466 Fast 1 Avg ± SD 2.0 ± 2.311.4 ± 11.8 11.3 ± 11.4 Range 0.2-5.9  1.1-30.0 11.1-29.1 Fast 2 Avg ±SD 3.6 ± 3.9 22.9-25.6 22.5 ± 24.9 Range 0.5-8.6  1.8-57.4  1.8-56.1 FedAvg ± SD 10.9 ± 12.7 38.2 ± 40.0 37.1 ± 38.9 Range  0.3-28.5  1.7-90.3 1.6-87.7 OPTIM. #4 PI-1495 Fast Avg ± SD 0.5 ± 0.5 2.5 ± 2.3 2.6 ± 2.4Range 0.1-1.4 5.9-0.3 0.3-5.7 Fed Avg ± SD 3.0 ± 6.7 10.2 ± 19.4 11.3 ±20.0 Range  0.1-19.4  0.2-57.0  0.2-55.4 Fed (-Subject 1) Avg ± SD 0.6 ±0.9 3.6 ± 4.9 4.0 ± 5.0 Range 0.1-2.5  0.2-13.8  0.2-13.4 PI-1496 FastAvg ± SD 1.2 ± 0.9 7.1 ± 4.6 7.0 ± 4.6 Range 0.1-2.7  0.6-14.2  0.6-14.5Fed Avg ± SD 2.7 ± 2.9 13.4 ± 12.6 13.1 ± 12.3 Range 0.1-7.6  0.1-31.6 0.4-30.7 OPTIM. #5 PI-1510 Fast Avg 0.4 2.0 3.9 Fed Avg 0.7 3.4 4.5

While the present invention has been described in terms of the preferredembodiments, it is understood that variations and modifications willoccur to those skilled in the art. Therefore, it is intended that theappended claims cover all such equivalent variations that come withinthe scope of the invention as claimed.

1. A multi-layer composition comprising: a. a water-soluble core; b. anantagonist containing layer comprising naltrexone or a pharmaceuticallyacceptable salt of naltrexone coating the core; c. a sequesteringpolymer layer coating the antagonist containing layer; d. an agonistlayer comprising morphine or a pharmaceutically acceptable salt ofmorphine coating the sequestering polymer layer; and, e. a controlledrelease layer coating the agonist layer; wherein the multi-layercomposition sequesters at least 80% of the naltrexone or thepharmaceutically acceptable salt of naltrexone as determined at 73 hoursby first placing the multi-layer composition in 500 mL of a 0.1 N HClsolution for 1 hour at 37° C. using USP paddle method, 100 rotations perminute, and then placing the multi-layer composition in 500 mL of a pH7.5, 0.05 M phosphate buffer, for 72 hours at 37° C. using USP paddlemethod, 100 rotations per minute, and then determining the amount of thenaltrexone or the pharmaceutically acceptable salt thereof sequestered;and wherein one of the following conditions are met: i) the agonistlayer comprises sodium chloride; or ii) the multilayer compositionfurther comprises, immediately beneath the agonist layer, an osmoticpressure regulating agent layer comprising sodium chloride.
 2. Themulti-layer composition of claim 1, wherein the antagonist containinglayer comprises the pharmaceutically acceptable salt of naltrexone,wherein the pharmaceutically acceptable salt of naltrexone is naltrexoneHCl; the sequestering polymer layer comprises copolymers of acrylic andmethacrylic acid esters with quaternary ammonium groups, sodium laurylsulfate in an amount from 1.6% to 6.3% of the copolymers of acrylic andmethacrylic acid esters with quaternary ammonium groups on aweight-to-weight basis, and talc in an amount of from 75% to 125% of thecopolymers of acrylic and methacrylic acid esters with quaternaryammonium groups on a weight-to-weight basis coating the antagonistcontaining layer; and the agonist layer comprises morphine sulfate andhydroxypropylmethyl cellulose.
 3. The multi-layer composition of claim2, wherein condition i) is met.
 4. The multi-layer composition of claim2, wherein condition ii) is met.
 5. The multi-layer composition of claim4, wherein the osmotic pressure regulating agent layer further compriseshydroxypropylmethyl cellulose.
 6. The multi-layer composition of claim1, wherein the multi-layer composition, after being orally taken by ahuman in the fed state, results in the human having an area under theplasma concentration versus time curve for 6-beta-naltrexol, at 168hours (AUC_(last)), of 1057 pg*h/mL.
 7. The multi-layer composition ofclaim 1, wherein the multi-layer composition, after being orally takenby a human, results in the human having a time to maximum concentrationfor 6-beta-naltrexol (T_(max)), in the human's plasma, of 57.29 hours.8. The multi-layer composition of claim 1, wherein the multi-layercomposition, after being orally taken by a human, results in the humanhaving a maximum concentration of 6-beta-naltrexol (C_(max)) in thehuman's plasma, of 25 pg/mL.
 9. The multi-layer composition of claim 1,wherein the controlled release layer comprises a cellulose; apolyalkylene glycol; an anionic copolymer based on methacrylic acid andethylacrylate; and a plasticizer.
 10. The multi-layer composition ofclaim 1, wherein the multi-layer composition does not contain abittering agent, a gelling agent, an irritant, or an emetic.
 11. Themulti-layer composition of claim 1, wherein the multi-layer compositioncontains the antagonist only in the antagonist containing layer.
 12. Themulti-layer composition of claim 1, wherein the multi-layer compositioncontains the agonist only in the agonist layer.
 13. The multi-layercomposition of claim 1, wherein in the multi layer composition, the onlyagonist is the morphine or the pharmaceutically acceptable salt thereof.14. The multi-layer composition of claim 1, wherein in multi-layercomposition, the only antagonist is the naltrexone or thepharmaceutically acceptable salt thereof.
 15. The multi-layercomposition of claim 2, wherein in the multi-layer composition, thesodium lauryl sulfate is only contained in the sequestering polymerlayer.
 16. The multi-layer composition of claim 1, wherein in themulti-layer composition, the sodium chloride is contained only in theagonist layer.